Nutritional supplementation [10, 11] and appetite stimulation [12, 13] can increase body weight and body fat in patients with HIV-associated wasting, but these treatments do not consistently restore lean tissue. The apparent failure of nutritional therapy to restore lean tissue suggests that, in some HIV-infected patients, metabolic alterations either promote nitrogen wasting or at least prevent repletion of lean tissue during periods when the patients presumably have adequate energy intake. Although increases in body fat in this setting may not be intrinsically harmful, body fat content is not correlated with survival [5, 7].

Thus, optimal therapy for patients with HIV-associated wasting should specifically reverse or forestall loss of lean tissue. Pharmacologic doses of growth hormone have induced nitrogen retention and increased protein synthesis and lean body mass in other catabolic states [14-17]. This treatment has also produced weight gain and nitrogen retention in a short-term study [18] of patients with HIV-associated wasting. The results of an open-label study [19] of a small group of patients with HIV-associated wasting suggested that growth hormone may have a sustained effect on lean body mass. We report the results of a randomized, multicenter, double-blind, placebo-controlled study that assessed the effects of growth hormone therapy on weight, body composition, functional performance, and quality of life in patients with HIV-associated wasting.

Methods

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Patients

Eligible patients were 18 years of age or older and had antibodies to HIV type 1, documented unintentional weight loss of at least 10% or weight less than 90% of the lower limit of ideal body weight [20], a Karnofsky score of 50 or greater, and life expectancy of 4 months or longer. Patients had to be able to consume at least 75% of maintenance energy requirement based on concurrent body weight. Patients had to have been receiving a stable regimen of antiretroviral therapy for at least 30 days before study entry and had to continue to receive antiretroviral therapy during the study.

Exclusion criteria included pregnancy; severe diarrhea ( 6 stools per day); use of anabolic agents, glucocorticoids, appetite stimulants, or parenteral or tube feeding; initiation of therapy for a systemic infection within 30 days of enrollment; an active malignant condition other than localized Kaposi sarcoma (<10 cutaneous lesions, <2 cm in diameter); recent radiotherapy or systemic chemotherapy; untreated hypertension; history of diabetes mellitus, significant cardiovascular disease, chronic edema, or the carpal tunnel syndrome; fasting glucose level greater than 6.7 mmol/L; triglyceride level greater than 5.6 mmol/L; amylase level more than 3 times the upper limit of normal; or hemoglobin level less than 85 g/L.

The study was approved by the institutional review board at each participating center, and signed informed consent was obtained before patients were enrolled. Baseline measures included results of history and physical examination; weight; body composition; assessment of treadmill work output and quality of life; routine hematologic and biochemical assessments; and measurement of insulin-like growth factor 1 levels, CD4⁺ and CD8⁺ lymphocyte counts, and p24 antigen levels. Plasma HIV RNA levels were measured in a subset of patients from whom appropriate samples were available.

Patients were randomly assigned to receive recombinant human growth hormone derived from mammalian cells (Serostim, Serono Laboratories, Norwell, Massachusetts), 0.1 mg/kg of body weight subcutaneously every evening (average dosage, 6 mg/d), or an equivalent amount of placebo. This dose of growth hormone caused weight gain and nitrogen retention in a short-term study of patients with HIV-associated wasting [18]. Patients were randomly assigned according to a computer-generated randomization list that was balanced across all patients and within sites. Kits that contained either the active study drug or placebo in identical vials were given to the study sites. Patients and investigators were blinded to the content of the vials until the study was complete. Patients were reevaluated at weeks 1, 2, 6, and 12; adverse events were recorded and laboratory assessments were done at these evaluations.

Doses were reduced for patients with fasting triglyceride levels greater than 7.9 mmol/L, fasting glucose levels greater than 8.9 mmol/L, moderate hypertension, arthralgia that did not respond to anti-inflammatory therapy, the carpal tunnel syndrome, edema that did not respond to diuretics, moderate systemic allergic reaction, or severe paresthesia. The dose was reduced by 50% and again by 50% if symptoms did not resolve within 10 days. Patients in whom symptoms persisted at the lowest dose were withdrawn from the study. Severe events that required suspension of treatment included fasting triglyceride levels of 16.9 mmol/L or greater, glucose levels of 22.2 mmol/L or greater, pseudotumor cerebri, congestive heart failure, pancreatitis, marked hypertension (blood pressure > 200/110 mm Hg), intolerable paresthesia, or severe systemic allergic reaction. If symptoms resolved within 5 days, patients could resume therapy at 50% of the dose used at the time of the event. Treatment was discontinued immediately and not resumed in patients who developed a new occurrence of cancer (including Kaposi sarcoma) and in patients who had progression of existing Kaposi sarcoma (new lesions or >50% growth of existing lesions). Patients who had acute infections could remain in the study at the discretion of the investigator.

Outcome Assessments

All measurements were done by investigators and their associates at each study site; investigators and associates were unaware of assignment to growth hormone or placebo. At baseline and 6 and 12 weeks, weight and body composition were measured after overnight fasting and voiding. Patients wore only a hospital gown. Weights were measured on the same calibrated scales (certified to have an accuracy to ± 0.2 kg and a coefficient of variation of 0.3%) throughout the study; the average of three determinations was used. Weight was also recorded at weeks 1 and 2 but not necessarily in the fasting state.

Body fat, lean body mass, and bone mineral content were measured by dual-energy x-ray absorptiometry [21-23] with either a Lunar model DPX (Madison, Wisconsin) or Hologics model QDR-1000W or QDR-2000W (Waltham, Massachusetts). Scanning was done with the same equipment and software throughout the study.

Total body water was measured by deuterium oxide dilution [24], and extracellular water was measured by sodium bromide dilution [25]. Plasma samples were collected at baseline and 3 hours after patients ingested 10 g of deuterium oxide and 5 g of 4 M sodium bromide. Patients fasted throughout the test period.

For assessment of work output, patients walked on a treadmill at increasing workloads according to an adaptation of a protocol for patients with limited exercise capacity [26]. Speed or grade was increased at 3-minute intervals, and exercise was terminated when patients reached volitional exhaustion or estimated maximal heart rate [26]. Work output was calculated from body weight and treadmill speed and grade [27].

Changes in overall health status, functioning, disability, and symptoms were assessed by having patients complete a visual analogue self-appraisal (on a scale of 1 to 10) of overall quality of life and a self-administered questionnaire, the HIV-Patient Assessed Report of Status and Experience (HIV-PARSE) [28]. The HIV-PARSE questionnaire contains modified items and scales from the Medical Outcomes Study that can be analyzed separately or as an overall index [29] and that have been shown to reflect differences in quality-of-life outcomes with HIV therapies [30].

Laboratory Assessments

Routine hematologic and biochemical variables were measured in the clinical laboratories at each site. Enrichment of deuterium oxide in plasma was determined by isotope ratio mass spectrometry [24]. Concentration of bromide in plasma was determined by ion chromatography [25]. Levels of plasma insulin-like growth factor 1 were measured by radioimmunoassay [31]. Levels of immune-complex dissociated p24 antigen were measured in acid-treated sera [32]; a change in p24 antigen levels was defined as an increase or decrease from baseline of 50% or greater, as long as one sample was 30 pg/mL or greater. Levels of HIV RNA in plasma were measured by branched-DNA assay [33, 34].

Statistical Analysis

Sample size was calculated to detect a 2% difference between groups in weight change at week 12 with at least 80% power for a two-sided test with 5% type I error, assuming an SD of ± 4%. The groups were compared at baseline using analysis of variance. Analysis of variance was also used to compare changes in weight and body composition in patients who had measurement at baseline and week 12 and at least 80% compliance with the dosing regimen. An intention-to-treat analysis using the Wilcoxon rank-sum test was done on changes from baseline to the last postbaseline value measured in each patient, regardless of whether they completed the study or complied with the dosing regimen. The Wilcoxon rank-sum test was also used to evaluate the change in work output during treadmill exercise. We investigated a treatment-by-center interaction for data that did not have a normal distribution by examining the median values of change from baseline body weight across all centers. For data that had a normal distribution, we compensated for a possible treatment-by-center effect in the analysis of variance model. Because no evidence suggested an interaction, the analyses were not done separately for each center.

Health status scores and other continuous data from the HIV-PARSE survey were analyzed using the Wilcoxon rank-sum test. Pearson correlation coefficients were calculated between change in work output during exercise and changes in lean body mass and body fat. Analysis of covariance was done to determine the predictive value of selected baseline characteristics on the change in lean body mass.

The groups were compared for rates of adverse events by using the Fisher exact test. Changes from baseline to end point (week 12 or the last available measure) for clinical and laboratory values were compared between groups by using unpaired t-tests. Patients who received at least one injection of the study drug were included.

Data are presented as the mean ±SD, median, and 95% CIs where appropriate. All analyses were done using SAS software, version 6.08 (SAS Institute, Cary, North Carolina).

Results

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Patient Characteristics

One hundred seventy-eight patients were enrolled at 12 centers between July 1992 and December 1993 (Table 1). Ninety patients were randomly assigned to receive growth hormone and 88 were assigned to receive placebo. Five patients (3 assigned to receive growth hormone and 2 to receive placebo) failed to meet the eligibility criteria for documented weight loss but were still included in the analysis. Weight, body composition, and severity of HIV infection did not differ significantly between groups. Most patients were in the advanced stages of HIV infection (average CD4⁺ lymphocyte count, <100 cells/mm³). The groups were balanced according to history of opportunistic infections. Of the 178 patients who were assigned to a group, 140 (79%) were considered evaluable for efficacy (69 patients assigned to the growth hormone group and 71 assigned to the placebo group). The number of days that the drug or placebo was administered did not differ (73 ± 23 days in the growth hormone group and 73 ± 25 days in the placebo group). We also found no significant differences between groups in the frequency or nature of changes in antiretroviral therapy during the study.

Body Weight

Treatment with growth hormone resulted in a significant and sustained increase in weight, but no net change was seen in the weight of patients given placebo (Figure 1). Weight change at week 12 was significantly greater in patients who received growth hormone (1.6 ± 3.7 kg) than in those who received placebo (0.1 ± 3.1 kg) (P = 0.011). According to the intention-to-treat analysis, the change in body weight also significantly differed between groups (growth hormone group: median, 1.8 kg and mean, 1.1 ± 4.0 kg; placebo group: median, 0.0 kg and mean, 0.1 ± 2.9 kg [P = 0.009]).

View larger version (12K): [in this window] [in a new window]   Figure 1. Effect of growth hormone or placebo on weight, lean body mass, and body fat in patients with human immunodeficiency virus-associated wasting. Data are the mean ± SE for the change in comparison with baseline values for evaluable patients receiving growth hormone (n = 69) or placebo (n = 71). Three patients in the placebo group were missing body composition measurements and thus were not induded. At week 12, weight, lean body mass, and body fat were significantly changed from baseline values in patients receiving growth hormone (P < 0.001). No significant differences were seen in these values for patients receiving placebo. Differences between treatment groups at week 12 were also significant (P = 0.011 for body weight; P < 0.001 for lean body mass and body fat).

Body Composition

Lean body mass increased significantly in patients receiving growth hormone and was unchanged in those receiving placebo (Figure 1). At week 12, the average increase in lean body mass in the growth hormone group was nearly twice that in body weight, and the difference between groups was highly significant (change of 3.0 ± 3.0 kg in the growth hormone group compared with –0.1± 2.0 kg in the placebo group [P < 0.001]). A similar difference was seen in the intention-to-treat analysis (growth hormone group: median, 3.0 kg and mean, 2.5 ± 3.4 kg; placebo group: median, 0.0 kg and mean, 0.1 ± 2.9 kg [P < 0.001]).

Body fat decreased significantly in patients treated with growth hormone and was unchanged in those given placebo (Figure 1). At week 12, the difference between groups was highly significant (change of –1.7± 1.7 kg in the growth hormone group compared with –0.3± 2.2 kg in the placebo group [P < 0.001]). A similar difference was seen in the intention-to-treat analysis (growth hormone group: median, –1.5 kg and mean, –1.7± 1.8 kg; placebo group: median, –0.1 kg and mean, –0.3± 2.1 kg [P < 0.001]). Bone mineral content was unaffected (data not shown).

Baseline measures of total body water, extracellular water, and intracellular water did not differ significantly between the two groups. Significant increases in these fluid compartments occurred in patients treated with growth hormone (P < 0.001 for total body water and intracellular water, P = 0.003 for extracellular water) but not in those given placebo (Table 2). The hydration coefficient (a ratio of total body water to lean body mass) and the ratios of extracellular water to lean body mass and extracellular water to intracellular water did not change significantly in either group and did not differ between groups (Table 2).

Functional Performance and Quality of Life

At baseline, work output and time to volitional exhaustion did not differ significantly between the two groups (Table 3). The change in work output at termination of exercise was significantly greater in patients treated with growth hormone (an increase of 13.2%) than in those given placebo (an increase of 2.5%) (Table 3). Intention-to-treat analysis resulted in a similar difference in the increase of work output (growth hormone group: median, 63 kg·m/min and mean, 67 ± 312 kg·m/min; placebo group: median, 0 kg·m/min and mean, 2 ± 229 kg·m/min [P = 0.038]). Because work output represents the product of speed, grade, and weight and because growth hormone increased weight, we calculated the proportion of the increase in work that was attributable to the increase in weight: Only 22% of the increase in work induced by growth hormone was attributable to the increase in weight. Thus, most of the increase in work output was attributable to increases in speed or grade. For all evaluable patients, changes in work output (r = 0.320; P < 0.001) and time to volitional exhaustion (r = 0.225; P = 0.012) correlated significantly with change in lean body mass but not with change in body fat.

Baseline scores on the health status scale were similar in both the treatment groups (Table 4). At 39 of 100 points, the overall score on the general health perceptions scale was lower than that reported in other populations of patients with HIV infection [30]. Average scores on the other scales were similar to those reported in similar populations [30]. In the intention-to-treat analysis, changes in scale scores were small and similar across scales and between groups. The average difference between baseline and end point on the scales that ranged from 0 to 100 was minimal. Days of disability and use of ambulatory, hospital, and home care services did not differ between the groups. Slightly more telephone contacts with health care providers were made by patients receiving growth hormone than by those receiving placebo (2.3 contacts/wk compared with 1.2 contacts/wk, respectively [P = 0.05]).

Factors Contributing to Treatment Effects

Baseline levels of serum insulin-like growth factor 1 were similar between groups (178 ± 71 ng/mL in the growth hormone group and 184 ± 83 ng/mL in the placebo group) but increased only in patients who received growth hormone (increase of 243 ± 240 ng/mL [n = 67] in the growth hormone group compared with decrease of 2 ± 79 ng/mL [n = 70] in the placebo group at week 12 [P < 0.001]). The changes in level of insulin-like growth factor 1 and lean body mass were significantly correlated in patients evaluable at week 12 (r = 0.393; P < 0.001).

When evaluated by analysis of covariance, only baseline CD4⁺ lymphocyte count and body mass index were significantly related to the change in lean body mass during treatment (P = 0.012 for baseline CD4⁺ lymphocyte count and 0.017 for body mass index). However, increases in lean body mass were seen at all levels of CD4⁺ lymphocyte counts and body mass index. The change in lean body mass during treatment was not related to baseline measures of age, Karnofsky score, percentage of ideal body weight, or duration of HIV infection or the presence of an AIDS-defining diagnosis other than wasting at baseline.

Safety

A similar number of patients prematurely withdrew from the study in both groups (Table 5). Two patients in the growth hormone group withdrew because of adverse events (one for edema and pain and one for arthralgias). Five patients (one in the growth hormone group and four in the placebo group) were withdrawn because of new or progressive Kaposi sarcoma; progressive Kaposi sarcoma was noted at week 12 in another patient treated with growth hormone. Eight patients (four in each group) had Kaposi sarcoma at baseline that did not progress during the study.

A new HIV-associated event was reported in 24 patients (10 in the growth hormone group and 14 in the placebo group); the most frequent event was Pneumocystis carinii pneumonia (3 in the growth hormone group and 5 in the placebo group). Five patients (3 in the growth hormone group and 2 in the placebo group) died as the result of an infection.

Among commonly reported side effects, only swelling or puffiness, arthralgia or myalgia, and diarrhea differed significantly between groups (Table 6). These events were usually mild to moderate in severity and resolved with treatment. Eighteen patients (15 in the growth hormone group and 3 in the placebo group) required a reduction in dose. Three patients who were receiving growth hormone developed the carpal tunnel syndrome. The syndrome resolved in 2 of the patients after a single dose reduction and in 1 despite continued treatment. Other commonly reported symptoms that are typical of advanced HIV infection did not differ between groups (Table 6).

Baseline laboratory measures did not differ significantly between groups (Table 7). Increases in glucose, hemoglobin A_1c, calcium, and phosphorus values associated with use of growth hormone were higher than those associated with use of placebo. These changes, which are a predictable response to growth hormone therapy, were minimal. In addition to the laboratory measures shown in Table 7, only serum alanine aminotransferase levels differed significantly between study groups. This difference appeared to be the result of one patient in the growth hormone group who developed severe hepatitis A virus infection.

No significant changes in CD4⁺ or CD8⁺ lymphocyte counts or plasma HIV RNA level occurred during the study (Table 7). In addition, mean changes in titers of infectious viremia in plasma, done in a subgroup of 21 patients at one site, did not significantly differ between treatment groups (data not shown). No change in immune-complex dissociated p24 antigen levels was noted in 84% of patients receiving growth hormone and 86% of patients receiving placebo (P > 0.2).

Discussion

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Treatment with growth hormone resulted in a sustained and significant increase in weight and lean body mass and a decrease in body fat in a large group of patients with HIV-associated weight loss. In contrast, weight and body composition were not altered in patients who received placebo. The increase in lean body mass and decrease in body fat that occurred after 3 months of growth hormone therapy in an outpatient setting are consistent with the short-term effects of growth hormone therapy on protein and lipid metabolism seen in a small group of patients who were hospitalized and fed a constant diet in a metabolic ward [18]. Growth hormone therapy is therefore effective as an anabolic agent even when administered to patients who consume diets that they select themselves under their usual living conditions.

In clinically stable patients infected with HIV, decreased body cell mass is associated with decreased physical function [3]. We found that the increase in lean body mass during treatment with growth hormone correlated with improvement in functional performance determined by work output during treadmill exercise. However, these changes were not reflected by changes in perceived health status or use of medical resources. A trend toward increased power of skeletal muscle and increased endurance was noted in a small group of HIV-infected patients who gained lean body mass when given growth hormone for a period similar to that of our study [19]. Similarly, strength [35, 36], work output [37], and lean body mass [35, 36, 38, 39] improved in studies of growth hormone replacement therapy in growth hormone-deficient adults.

Current therapies for HIV-associated anorexia or weight loss include nutritional supplements and therapy with appetite-stimulating drugs such as megestrol acetate and dronabinol. Of these, dronabinol has failed to consistently increase weight [40, 41], and the others have failed to consistently restore lean tissue [11-13]. Because lean tissue and not fat may independently affect survival [5-7] and function [3] in patients with HIV-associated wasting, the sustained increase in lean body mass that we found suggests a potential advantage for growth hormone as anabolic therapy. For example, although patients with HIV-associated weight loss gained an average of 3.0 kg while receiving total parenteral nutrition, body fat increased by 3.9 kg and total body potassium levels (an index of body cell mass) did not change [11]. A similar disproportionate increase in body fat with minimal or no accrual of lean tissue occurs when patients with HIV-associated wasting are given an appetite stimulant. In one recent trial [13], treatment with megestrol acetate (800 mg/d for 12 weeks) resulted in a 4.5-kg increase in body fat and no change in lean body mass. In another trial [12], patients gained an average of 3.5 kg but only 1.1 kg of lean body mass (the remainder, by inference, was fat). These minimal or negligible changes in lean body mass contrast with the 3.0-kg increase noted during therapy with growth hormone.

The growth hormone-induced increase in total body water (2.4 L by dilution analysis) was similar to the value predicted through the observed increase in lean body mass (3.0 kg by dual-energy x-ray absorptiometry) and the proportion of lean body mass as total body water (0.75 L/kg) at baseline (Table 2). Because the ratios of total body water to lean body mass, extracellular water to lean body mass, and extracellular water to intracellular water did not change significantly, the expansion in lean body mass included intracellular and extracellular water in a proportion similar to that at baseline. Because intracellular water is the most direct measure of body cell mass [42], the expansion in intracellular water that we found suggests that growth hormone increased metabolically active tissue.

Our results provide no evidence of a deleterious effect of growth hormone on HIV replication as measured by HIV RNA levels in plasma, immune-complex dissociated p24 antigen levels, and titers of infectious viremia in plasma. Concern about a potential effect of growth hormone on HIV replication was prompted by the increase in release of p24 antigen from phytohemagglutinin-activated, HIV-infected mononuclear cells from peripheral blood seen in incubation with growth hormone [43]. This effect varied, however, and could be inhibited by adding zidovudine to the culture media. Despite the absence of evidence that growth hormone promotes replication of HIV in vivo, concomitant treatment with approved antiretroviral agents was a requirement for our study and in ongoing trials of growth hormone in this patient population.

A theoretical concern could also be raised about a possible tumor-promoting effect of growth hormone use in patients with HIV infection [44]. However, review of the extensive data obtained on children treated with growth hormone does not support a relation with either new types of cancer or tumor recurrence [45, 46]. No difference was seen in the rate of occurrence or progression of AIDS-associated neoplasms between the growth hormone and placebo groups.

Overall, growth hormone was well tolerated. Side effects that may have been related to growth hormone were mild, did not negatively affect quality of life, and generally responded to reductions in dose. The rates of withdrawal and serious adverse events did not differ significantly between treatment groups. Together with the sustained increases in body weight and lean body mass and increased functional performance, these results indicate that growth hormone may be a useful therapy in patients with HIV-associated wasting. Although the cost of this therapy has not been established, a 12-week course of treatment currently approved by the Food and Drug Administration under the auspices of an expanded access program costs approximately $12 000. An analysis of the implications of the cost of this and other new therapies in patients with HIV infection should consider the potential savings gained from any improvement in quality of life, increase in work days, and reduction in HIV-associated complications resulting from the therapy, as future studies might show.

Appendix

The following persons participated in the Serostim Study Group: A. Hurley and K. Javaly (Bellevue Hospital, New York, New York); E.S. Daar and J. Pitt (Cedars-Sinai Medical Center, Los Angeles, California); C. Grunfeld and M. Pang (Department of Veterans Affairs Medical Center, San Francisco, California); A.E. Heald and K.W. Shipp (Duke University Medical Center, Durham, North Carolina); D. Pearce and K. Sova (HIV Research Group, San Diego, California); P. Pate (ID Associates, Dallas, Texas); S.L. Boswell and T. Flynn (Massachusetts General Hospital, Boston, Massachusetts); B. Polsky (Memorial Sloan-Kettering Cancer Center, New York, New York); L. Haverstick and M.M. Rothkopf (Metabolic Associates, Florham Park, New Jersey); D.L. Bliffen (Metroplex Clinical Research Center, Dallas, Texas); R. Rosenfeld (Oregon Health Sciences University, Portland, Oregon); D.P. Kotler, R.N. Pierson Jr., J. Wang, and G. Winson (St. Luke's-Roosevelt Hospital Center, New York, New York); K. Mulligan, M. Schambelan, and V. Tai (San Francisco General Hospital, San Francisco, California); W.M. Bennison, J.B. Breitmeyer, S.M. Kennedy, T.K. Neu, C.E. Robinson, and R.J. Schwalbert (Serono Laboratories, Inc., Norwell, Massachusetts); A. LaMarca and D. LaMarca (Therafirst Medical Center, Ft. Lauderdale, Florida); S.A. Bozzette (University of California, San Diego, California); D.R. Kuritzkes and M.G. Ray (University of Colorado Health Services Center, Denver, Colorado); J.W. Mellors (University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania); B.E. Balser and J.P. Balser (Veristat, Inc., Holliston, Massachusetts).

This paper was presented in part in August 1994 at the 10th International Conference on AIDS, Yokohama, Japan.

From San Francisco General Hospital; Department of Veterans Affairs Medical Center; and University of California, San Francisco, San Francisco, California; Cedars-Sinai Medical Center and University of California, Los Angeles, Los Angeles, California; Therafirst Medical Center, Fort Lauderdale, Florida; St. Luke's-Roosevelt Medical Center and Columbia University, New York, New York; Department of Veterans Affairs Medical Center and University of California, San Diego, San Diego, California; and Serono Laboratories, Norwell, Massachusetts.

Dr. Grunfeld: Department of Veterans Affairs Medical Center 111F, 4150 Clement Street, San Francisco, CA 94121.

Dr. Daar: Cedars-Sinai Medical Center, Division of Infectious Diseases, B217, 8700 Beverly Boulevard, Los Angeles, CA 90048.

Dr. LaMarca: Therafirst Medical Center, 4011 North Federal Highway, Fort Lauderdale, FL 33308.

Dr. Kotler: G.I. Immunology, St. Luke's-Roosevelt Hospital Center, 1111 Amsterdam Avenue, New York, NY 10025.

Mr. Wang: Body Composition Unit, St. Luke's-Roosevelt Hospital Center, 1111 Amsterdam Avenue, New York, NY 10025.

Dr. Bozzette: San Diego Veterans Affairs Medical Center 111N1, 3350 La Jolla Village Drive, San Diego, CA 92161.

Dr. Breitmeyer: Serono Laboratories, Inc., 100 Longwater Circle, Norwell, MA 02061.