JAIDS Journal of Acquired Immune Deficiency Syndromes:
Oxandrolone in the Treatment of HIV-Associated Weight Loss in Men: A Randomized, Double-Blind, Placebo-Controlled Study
Grunfeld, Carl MD, PhD*; Kotler, Donald P. MD†; Dobs, Adrian MD‡; Glesby, Marshall MD§; Bhasin, Shalender MD∥; for the Oxandrolone Study Group
From the *University of California, San Francisco, and the Department of Veterans Affairs Medical Center, San Francisco, CA; †St. Lukes- Roosevelt Medical Center, Columbia University School of Medicine, New York, NY; ‡Johns Hopkins School of Medicine, Baltimore, MD; §Community Research Initiative on AIDS, New York, NY and ∥Charles Drew University of Medicine and Science, Los Angeles, CA.
Received August 3, 2005; accepted November 10, 2005
Grant support provided by Biotechnology General (now Savient Pharmaceuticals).
Reprints: Carl Grunfeld, Metabolism section (111F), Department of Veterans Affairs Medical Center, 4150 Clement Street, San Francisco, CA 94121 (e-mail: firstname.lastname@example.org).
Objective: To evaluate the efficacy and safety of oxandrolone in promoting body weight and body cell mass (BCM) gain in HIV-associated weight loss.
Methods: Randomized, double-blind, placebo-controlled trial. Two hundred sixty-two HIV-infected men with documented 10% to 20% weight loss or body mass index ≤20 kg/m2 were randomized to placebo or to 20, 40, or 80 mg of oxandrolone daily. After 12 weeks, subjects were allowed to receive open-label oxandrolone at a dose of 20 mg for another 12 weeks.
Results: Body weight increased in all groups, including the group receiving placebo, during the double-blind phase (1.1 ± 2.7, 1.8 ± 3.9, 2.8 ± 3.3, and 2.3 ± 2.9 kg in placebo and 20-, 40-, and 80-mg oxandrolone groups, respectively; all P < 0.014 vs. baseline). BCM increased from baseline in all groups (0.45 ± 1.7, 0.91 ± 2.2, 1.5 ± 2.5, and 1.8 ± 1.8 kg in placebo and 20-, 40-, and 80-mg oxandrolone groups, respectively). At 12 weeks, only the gain in weight at the 40-mg dose of oxandrolone and the gain in BCM at the 40- and 80-mg doses of oxandrolone were greater than those in the placebo group, however. Oxandrolone treatment was associated with significant suppression of sex hormone-binding globulin, luteinizing hormone, follicle-stimulating hormone, and total and free testosterone levels. Treatment was generally well tolerated but accompanied by significant increases in transaminases and low-density lipoprotein as well as decreases in high-density lipoprotein.
Conclusion: Oxandrolone administration is effective in promoting dose-dependent gains in body weight and BCM in HIV-infected men with weight loss.
Although the prevalence of weight loss in HIV-infected patients has decreased in developed nations with widespread use of antiretroviral drug therapy, weight loss continues to be a significant problem, affecting 31% of patients during the course of their illness.1-4 In Africa and Asia, where most HIV-infected patients reside, weight loss isa major presenting feature of AIDS.5 Weight loss and, in particular, loss of body cell mass (BCM) are independent riskfactors for death in patients with HIV infection, even when the CD4 cell count and history of complications are taken into account.5-11 Furthermore, loss of weight, lean body mass, and BCM are accompanied by decreased function, worsening quality of life (QOL), and increasing hospitalization rates.12-15
Early studies suggested that BCM was preferentially lost and fat spared in men with HIV-associated wasting.16 Whereas some subsequent studies had similar findings,8,17 other studies in men and women found more significant loss of fat.18-21 An explanation for these discrepancies is that subjects who had a low percentage of fat when first studied lost predominantly lean body mass, whereas those who started with higher percentage fat lost predominantly fat.20
Nutritional therapy and appetite stimulants can promote weight gain in patients with HIV-associated wasting.22-25 The predominant gain is in body fat, however. Although increased energy stores may reduce loss of BCM in future episodes of weight loss,18 body fat stores do not correlate with survival.6,8,9 In contrast, anabolic therapy with growth hormone (rhGH) has the potential of inducing gain of lean body mass; however, rhGH therapy also induces loss of fat reserves.26-29
Testosterone supplementation increases fat-free mass and muscle strength in HIV-infected men with mild to moderate weight loss.30-37 Androgenic steroids promote a positive nitrogen balance and weight gain (or amelioration ofweight loss) in other catabolic illnesses, including acute alcoholic hepatitis, cancer, end-stage renal disease, and burns.38-51 In studies of small numbers of patients with HIV-associated wasting, orally administered androgens, such as oxandrolone and oxymetholone, and the parenterally administered androgen nandrolone decanoate have induced significant weight gain.43-51 Given the potential advantage of an orally administered anabolic therapy, such as oxandrolone, we undertook a double-blind, placebo-controlled, randomized trial of graded doses of oxandrolone in HIV-infected subjects with weight loss, testing its effects on weight gain, body composition, total work capacity, health-related QOL, and safety.
Signed informed consent was obtained from each patient before entry under protocols approved by the institutional review board at each participating center. This was a randomized, placebo-controlled, parallel-group, double- blind, multisite clinical trial conducted at 25 sites between September 25, 1996 and July 20, 1998.
Eligible subjects were HIV-infected men ≥18 years of age who had 10% to 20% unintentional weight loss from premorbid weight documented in medical records or a body mass index (BMI) ≤20 kg/m2, a Karnofsky Performance Scale score >60%, a life expectancy of >6 months, and the ability to consume a normal well-balanced diet at entry as assessed by a dietitian. Therapy with antiretroviral medication was not required; however, subjects on antiretroviral therapy had to be on a stable regimen for more than 6 weeks at the time of entry.
Exclusion criteria included any opportunistic infection within 60 days of enrollment; loss of >5% body weight in the previous 30 days; chronic fever >101°F with a frequency ≥3days per week for at least 2 weeks in the previous 30 days; aspartate aminotransferase (AST), alanine aminotransferase (ALT), or alkaline phosphatase levels greater than 5 times the upper limit of normal and/or bilirubin level ≥2.0 mg/dL within 2 weeks; serum creatinine >2.0 mg/dL; known impaired digestive or absorptive function; chronic uncontrolled diarrhea (>3 liquid stools per day at least 4 days per week for >2 weeks); current treatment with anticoagulants or oral hypoglycemic agents; or treatment with appetite stimulants, weight-promoting agents, anabolic steroids, or testosterone in the previous 4 weeks. This dose-ranging study did not include women, because it was not known whether doses of this magnitude would cause significant virilization inwomen.
Treatment Assignment and Randomization
Subjects were assigned in concealed randomization (1:1:1:1) balanced at each center to placebo (4 tablets) or to 20 mg/d of oxandrolone (1 20-mg tablet of oxandrolone and 3placebos), 40 mg/d (2 20-mg tablets of oxandrolone and 2placebos), or 80 mg/d of oxandrolone (4 20-mg oxandrolone tablets) provided by Savient Pharmaceuticals (East Brunswick, NJ [formerly Bio-Technology General, Corporation]). Investigators and patients were blinded to treatment assignment during the initial 12 weeks. After 12 weeks, all subjects who wished to continue were placed on 20 mg of oxandrolone in an open-label continuation.
Two hundred sixty-two patients were randomized and included in the intent-to-treat analysis (placebo [n = 65], 20mg of oxandrolone [n = 64], 40 mg of oxandrolone [n = 65], and 80 mg of oxandrolone [n = 68]). Of these, 195 subjects completed the double-blind phase and 193 completed the open-label phase. Of the 67 subjects who discontinued treatment during the double-blind phase, 12 were in the placebo group, 18 were in the 20-mg oxandrolone group, 18were in the 40-mg oxandrolone group, and 19 were in the 80-mg oxandrolone group. Reasons for discontinuations included adverse experience,20 death,6 intercurrent medical problem or disease-related complication,2 subject relocation or voluntary patient withdrawal,21 and noncompliance.18
Measurements were made at baseline and at 2, 4, 8, and 12 weeks in the double-blind placebo phase and at weeks 14, 18, and 24 in the open-label study. The primary outcome waschange in body weight measured at each time point under standardized conditions (at the same time, preferably in themorning, wearing only underwear and socks) on a single balance-type scale that had been recently calibrated by a state agent or third-party source. Other outcomes included measurement of fat and BCM by bioelectrical impedance analysis (BIA) (RJL Systems). Because changes in hydration status and technical aspects of performance affect BIA, datawere excluded if the change in BCM was >2.5 times the change in weight or the change in BCM was >7.5 kg in a subject; 18 subjects were thus excluded from the body composition analysis because of quality control problems with BIA measurements (6 from placebo group, 3 from 20-mg oxandrolone group, 6 from 40-mg oxandrolone group, and 3 from 80-mg oxandrolone group). Health-related QOL was measured by the Medical Outcomes Study (MOS) HIV health survey.52 Treadmill tests were performed at centers with treadmill capability on day 1 and at weeks 4 and 12. Changes in physical capacity were assessed by changes in total workload from the treadmill tests. Nineteen percent of subjects had treadmill tests performed at week 12. Total workload is defined as Σ[speed (m/min)] [% grade/100] [time in minutes on treadmill].
Safety assessments, including HIV RNA levels by reverse transcriptase polymerase chain reaction (RT-PCR), CD4 T-lymphocyte counts, complete blood cell counts, and blood chemistry, were measured at Covance Laboratories.
Serum luteinizing hormone (LH), follicle-stimulating hormone (FSH), and sex hormone-binding globulin (SHBG) as well as testosterone levels were measured by 2-site-directed immunofluorometric assays (Delfia-Wallac, Gaithersburg, MD), with sensitivities of 0.05 U/L, 0.15 U/L, and 6.25 nmol/L, respectively, as described previously.53,54 The intra- and interassay coefficients of variation were 10.7% and 13.0% for LH, 3.2% and 11.3% for FSH, and 10.0% and 10.2% for SHBG, respectively. The cross-reactivity of free α-subunit and other pituitary hormones in the LH and FSHassays was <1%.
Serum total testosterone levels were measured using a radioimmunoassay (RIA) with an iodinated testosterone tracer54,55 that has been validated against liquid chromatography-mass spectrometry tandem mass spectrometry. This assay has a sensitivity of 0.44 ng/dL and intra- and interassay coefficients of variation of 8.2% and 13.2%, respectively. Free testosterone levels were measured by a sensitive equilibrium dialysis method,54,55 optimized to measure low concentrations with accuracy. Two hundred microliters of serum in the inner compartment was dialyzed against 2.4 mL of dialysis buffer that approximates the composition of a protein-free ultrafiltrate of human serum. Dialysis was performed overnight for 16 hours at 37°C. Testosterone concentration in the dialysate was measured by RIA using 125I-labeled testosterone. The sensitivity of the free testosterone assay is 0.6 pg/mL (2.0 pmol/L), with intra- and interassay coefficients of variation of 4.2% and 12.3%, respectively.
Total and free testosterone concentrations were not consistently changed during oxandrolone treatment despite suppression of LH concentrations, suggesting that oxandrolone or one of its metabolites might have cross-reacted in the testosterone assays. Therefore, we established a chromatographic system to separate testosterone from oxandrolone before RIA. Serum samples were extracted using ethyl acetate and hexane (3:2 vol/vol) and subjected to chromatography on celite columns equilibrated in isooctane. Lipemic samples were clarified by centrifugation before extraction. Testosterone was eluted by washing columns with 10% ethyl acetate in isooctane. In preliminary experiments, we demonstrated that >90% of 14C-testosterone eluted with 10% isooctane, whereas >90% of 3H-oxandrolone eluted with ≥15% iso-octane. Less than 5% of 14C-oxandrolone eluted with 10% isooctane; conversely, less than 5% of testosterone eluted at isooctane concentrations ≥15%. Eluates were dried under nitrogen and taken up in assay buffer. Recovery of known amounts of testosterone added tocharcoal-stripped serum samples during extraction and celite chromatography was consistently better than 80%. Therefore, values were not corrected for losses during chromatography.
At each visit, intercurrent illnesses, symptoms, and additional medicines were recorded. Compliance was assessed by pill count.
Results are presented as mean ± standard deviation (SD). Primary efficacy end points were changes in body weight and body composition from baseline. Based on preliminary data, the study was designed to detect a 2.0-kg (SD = 3.5 kg) increase in oxandrolone-treated patients compared with patients treated with placebo with a power of 80%, under the presumption that those on placebo would, on average, lose weight during the course of the study. The study was not powered to detect significant changes in secondary end points, such as quality of life. Analysis of variance (ANOVA) and the Dunnett t test were used to analyze primary and secondary efficacy parameters. To control the overall type 1 error rate of 0.05 for the multiple comparisons, Bonferroni inequality was used; treatment differences were considered significant if the significance level for that comparison was <0.017 instead of 0.05. Within-treatment changes from baseline were tested using a 1-way t test. The number of patients with adverse events and discontinuations was compared using the Fisher exact test. The prevalence of World Health Organization (WHO) grade III and IV toxicities was compared with placebo using the χ2test, with differences across dosages analyzed by the Cochran-Armitage trend test. Demographic and disease history variables at baseline were compared between treatment groups using ANOVA. The effect of race was tested using the χ2 test.
Baseline characteristics of the subjects were not significantly different among treatment groups (Table 1). Seventy percent of participants were white, 17% were African American, 11% were Hispanic, and 2% were other. Weight loss before entry averaged 16.4% ± 8.0% from baseline.
Body Weight and Composition
In subjects who were evaluated at baseline and received drug, weight increased progressively in all groups, including the placebo group, during the study (Fig. 1A). A significant increase occurred as early as 2 weeks after baseline for each group, including the placebo group. On an intent-to-treat basis at 12 weeks or at last measurement during the double-blind placebo phase, for the 258 subjects with baseline weight (Table 2), there was a gain of 1.1 ± 2.7 kg on placebo, 1.8 ± 3.9 kg on 20 mg of oxandrolone, 2.8 ± 3.3 kg on 40 mg of oxandrolone, and 2.3 ± 2.9 kg on 80 mg of oxandrolone (all P< 0.014 vs. baseline). Weight gain at 2, 4, 8, and 12 weeks on the 40-mg dose of oxandrolone was statistically different from weight gain on placebo (P = 0.0040 vs. placebo at 12 weeks). The difference in weight gain between the 80-mg oxandrolone group and the placebo group was significant at 4 and 8 weeks but not at 2 or 12 weeks (P = 0.045 at 12 weeks, which did not meet the multiple comparisons criterion). There was no significant effect of performance site.
Body composition was measured by using BIA. Thirty patients at 4 centers underwent dual energy x-ray absorptiometry (DEXA) measurements to validate body composition measurements by BIA. The correlation between the measurements of fat-free mass by the 2 methods was 0.937 (P < 001).
BCM increased progressively and significantly in all groups (see Fig. 1B). At 12 weeks or last visit on an intent-to-treat basis, the increase in BCM was 0.45 ± 1.7 kg on placebo, 0.91 ± 2.2 kg on 20 mg of oxandrolone, 1.5 ± 2.5 kg on 40 mg of oxandrolone, and 1.8 ± 1.8 kg on 80 mg of oxandrolone (see Table 2). The increase in BCM on the 40-mg and 80-mg doses at 12 weeks was significantly greater than that on placebo (P = 0.0049 and P = 0.0002, respectively). Similar results were obtained when intracellular water was analyzed by BIA (see Table 2). In contrast, there were nosignificant changes in extracellular water in any group (seeTable 2). There was also a trend to gain body fat on the40-mg dose, but this did not reach statistical significance using the multiple comparisons criteria.
The entry criteria included 10% to 20% of unintentional loss of weight or a BMI ≤20 kg/m2. These criteria allowed patients who were over their ideal body weight or even obese at baseline to enter the study if they had lost 10% to 20% of their body weight. Five subjects were obese (>120% ideal body weight), with the highest weight at entry being 107 kg. Twenty-four percent of the patients had a BMI >22.5 kg/m2. Therefore, we performed post hoc analysis evaluating changes in body weight and composition in subjects with a BMI ≤22.5 kg/m2 on an intent-to-treat basis at 12 weeks or last measurement. Their weight increase over baseline at 12 weeks was 0.8 ± 2.7 kg on placebo, 2.7 ± 4.0 kg on 20 mg of oxandrolone, 2.9 ± 2.6 kg on 40 mg of oxandrolone, and 2.5 ± 2.8 kg on 80 mg of oxandrolone (all significantly increased over baseline). Compared with placebo, subjects receiving 20mg, 40 mg, or 80 mg of oxandrolone had significantly higher weights at week 12 (P = 0.0026, P = 0.0005, and P = 0.0041, respectively). Similar changes were found for BCM,where the increases at 12 weeks over baseline were 0.2 ± 1.5 kg in the placebo group, 1.1 ± 2.1 in the 20-mg oxandrolone group; 1.8 ± 1.5 kg in the 40-mg oxandrolone group, and 2.0 ± 1.7 kg in the 80-mg oxandrolone group. Compared with placebo, subjects receiving 20, 40, or 80 mg of oxandrolone had a significantly higher BCM at week 12 (P= 0.0122, P < 0.0001, and P < 0.0001, respectively).
No significant differences were seen in MOS HIV health surveys for any treatment group. There was no significant change from baseline in total work output in the subset of subjects who underwent treadmill testing in any treatment group. There was no correlation between change in weight and QOL score or total work output.
Neither HIV RNA by RT-PCR nor CD4+ lymphocyte count was significantly affected by oxandrolone (Table 3). There were no significant changes in hemoglobin and white blood cell counts. However, there was a dose-dependent increase in platelet count (P < 0.017 for all doses of oxandrolone vs. placebo). There were small but significant increases in levels of creatinine and creatine kinase but not in blood urea nitrogen (BUN) in the oxandrolone groups compared with the placebo group.
Serum albumin, total protein, bilirubin, alkaline phosphatase, lactate dehydrogenase (LDH), and gamma-glutamyl transferase (GGT) levels were not significantly changed (see Table 3). However, there were dose-dependent increases in AST and ALT appearing by the first 4 to 8 weeks of therapy. The increase in AST was significant at the 80-mg dose compared with baseline, whereas the increase in ALT was significant at the 40-mg and 80-mg doses. Furthermore, there was a dose-related increase in the incidence of WHO grade III and IV liver toxicity for ALT and AST with increasing dose of oxandrolone (Table 4). For AST, WHO grade III and IV toxicity occurred in 2 of 61 subjects on placebo, 2 of 60 on 20 mg of oxandrolone, 6 of 61 on 40 mg of oxandrolone, and 9 of 61 on 80 mg of oxandrolone. For ALT, WHO grade III and IV toxicity occurred in 1 of 61 subjects on placebo, 3 of 60 on 20 mg of oxandrolone, 7 of 61 on 40 mg of oxandrolone, and 9 of 61 on 80 mg of oxandrolone (for trend, P = 0.0047). Three subjects receiving the 40-mg dose and 4 subjects receiving the 80-mg dose were discontinued from the drug because of laboratory abnormalities.
Glucose, triglyceride, and total cholesterol levels in patients receiving oxandrolone were not significantly different from those receiving placebo (see Table 3). There was a significant decrease in uric acid and plasma high-density lipoprotein (HDL) cholesterol levels at all doses. Furthermore, there was a significant increase in low-density lipoprotein (LDL) cholesterol levels at the 40-mg and 80-mg doses.
Six patents died during the placebo-controlled study (see Table 4), and 3 more died during the open-label phase or within 30 days of last receiving study medication during the placebo-controlled phase. Of the 9 subjects who died, 2 were on placebo, 3 were on 20 mg of oxandrolone, 2 were on 40 mg of oxandrolone, and 2 were on 80 mg of oxandrolone. There were no significant differences between the treatment groups in the numbers of infections, serious adverse events (SAEs), or milder adverse events. Seven SAEs were reported in 6 subjects on placebo, 20 SAEs were reported in 13 subjects on 20 mg of oxandrolone, 24 SAEs were reported in 14 subjects on 40 mg of oxandrolone, and 20 SAEs were reported in 14 subjects on 80 mg of oxandrolone. One hundred eighty-one different types of infections and adverse events were reported.
Overall dropout rates were similar among treatment groups (see Table 4). In some subjects, treatment discontinuation was prompted by more than 1 reason. There was a trend toward increased dropout because of an adverse experience or abnormal laboratory test results in the 40-mg and 80-mg oxandrolone groups attributable to treatment discontinuation for WHO grade III and IV elevations in AST and ALT.
Baseline total testosterone levels averaged close to the lower limits of normal (270 ng/dL; Table 5). At 12 weeks, serum LH and FSH concentrations decreased significantly from baseline in all oxandrolone-treated groups, consistent with an androgenic action. Serum SHBG concentrations also decreased with increasing doses of oxandrolone, which also suggests an androgenic effect of oxandrolone (SHBG was determined in a subset of patients, and total testosterone levels in the subset were similar to those in the larger cohort; data not shown).
Total and free testosterone concentrations measured bydirect RIA did not show a dose-related change. We used celite chromatography to separate testosterone from oxandrolone before RIA and found that serum total testosterone concentrations were significantly decreased from baseline at all doses of oxandrolone but not with placebo treatment (see Table 5).
After the double-blind placebo-controlled study, a subset of subjects opted to take 20 mg of oxandrolone in an open-label study. All 4 groups receiving 20 mg of oxandrolone during this 12-week open-label phase continued to gain weight (Table 6). By the end of the open-label phase, there were no significant differences in weight gain among the groups. AST levels decreased; although AST levels remained above baseline, they were no longer significantly different from baseline (see Table 6).
Oxandrolone treatment was associated with significantly greater body weight gain above baseline than with placebo. A major portion of this weight gain occurred in the lean body compartment, as reflected in the significant gains in BCM, intracellular water, and serum creatinine levels. The gains in body weight during the double-blind phase of the study were sustained during the open-label phase of the study.
Oxandrolone administration has been shown to increase muscle protein synthesis in emaciated burn patients,56 muscle mass and maximal voluntary strength in older men at risk for sarcopenia,57-60 and weight in patients with cancer cachexia. Most previous studies have included small numbers of subjects, however; this study is the largest randomized placebo-controlled trial of an androgen in patients with HIV-associated weight loss.
Serum LH and FSH levels decreased significantly during oxandrolone administration, consistent with its androgenic activity. Whereas conventional measurement of testosterone did not show consistent decreases, assay after chromatographic separation did show suppression of testosterone, confirming the androgenic effect and indicating that oxandrolone or a metabolite cross-reacted in the conventional testosterone assay. This dose-ranging study did not include women; therefore, we cannot determine whether the level of androgenic activity seen with oxandrolone would have the expected detrimental virilizing effects in women.
Oxandrolone administration was generally well tolerated. Grade III and IV elevations of transaminases were observed in >5% of study participants, however, especially atthe80-mg dose. Careful monitoring of these parametersistherefore indicated after the initiation of oxandrolone therapy. Furthermore, LDL levels increased and HDL levels decreased.
There has been considerable debate about what magnitude of change in body weight is clinically meaningful. An AIDS Clinical Trial Group (ACTG) expert panel on HIV-associated wasting expressed the opinion that a gain of 1.5 kg is clinically meaningful (Fred Sattler, MD, personal communication). The average weight gain at each of the oxandrolone doses exceeded 1.5 kg, whereas the increase in the placebo group was less than 1.5 kg. Only the 40-mg dose of oxandrolone induced more than a 1.5-kg increase in weight over that attained with placebo (an increase over placebo of 1.7 kg based on a 2.8-kg increase for 40 mg of oxandrolone vs. a 1.1-kg increase for placebo). For subjects whose BMI was ≤22.5 kg/m2, all 3 doses of oxandrolone induced more than a 1.5-kg increase over placebo (20 mg induced a 1.9-kg increase, 40 mg induced a 2.1-kg increase, and 80 mg induced a 1.7-kg increase). In subjects whose BMI was ≤22.5 kg/m2, the mean increases in BCM in patients treated with the 40- or 80-mg dose of oxandrolone were also greater than 1.5 kg above that attained with placebo. These changes in weight and BCM compare favorably with those observed during administration of rhGH27,28 and testosterone.31-36 In a meta-analysis of placebo-controlled, randomized, clinical trials of testosterone, the average gain in lean body mass was 1.3 kg in testosterone-treated HIV-infected men.61
In spite of significant body weight gains and lean mass accretion, total work output during treadmill exercise did not significantly change during treatment. This is consistent with the growing body of data that androgenic steroids increase muscle mass but do not affect measures of endurance, such as treadmill performance.62-64 Reports of randomized clinical trials published subsequent to the initiation of this study have reported significant gains in maximal voluntary strength with androgen supplementation of HIV-infected men with weight loss35; gains in muscle strength are generally proportional to increases in muscle mass.35
Participants in this study were able to consume a well-balanced diet at study entry as assessed by a dietitian. In developing countries of Africa and Asia, many HIV-infected patients have an overall energy deficit, with varying macro- and micronutrient deficiencies. We do not know whether androgen administration would be efficacious in preventing weight loss in HIV-infected patients with severe wasting or in nutritionally depleted individuals.
Administration of oxandrolone has been associated with significant decreases in plasma HDL cholesterol levels and increases in LDL cholesterol levels.60,65,66 The administration of the 40- and 80-mg doses was associated with significant increases in ALT and AST; these increases were transient and returned toward baseline in most subjects. Treatment discontinuations attributable to persistent and marked increases in transaminases were common and occurred in more than 5% of individuals. We found no increase in bilirubin or alkaline phosphatase.
The gains in body weight and BCM were related to oxandrolone dose. Similarly, there were dose-dependent increases in AST and ALT levels and common treatment discontinuations attributable to AST and ALT elevations. Thus, the best trade-off between the anabolic effects and AST and ALT elevation was achieved at the 40-mg daily dose. The therapeutic efficacy and safety of this dose should be further evaluated in subsequent clinical trials.
The decreases in HDL and increases in LDL represent a proatherogenic lipoprotein profile. Clinicians therefore need to weigh the risk-benefit ratio of this therapy. Wasting syndrome predicts a significant risk of complications and death, but even studies as large as this one are not large enough and have not been carried out long enough to determine whether reversal of that risk occurs with treatment of wasting and to determine the risk of cardiovascular disease. The risk of atherosclerosis predicted by this lipoprotein profile suggests that such therapy should be restricted to those with significant wasting or should be terminated when wasting has improved. Mean CD4 lymphocyte counts in this study were >200 × 106/L, which is higher than in most earlier studies of HIV-associated wasting (which often had mean values ≤50 × 106/L), indicating better health later in the epidemic. In that light, future studies should likely exclude those with obesity even in the presence of weight loss. In post hoc analysis, we found that the 20-mg dose was more effective in those with a BMI at entry of ≤22.5 kg/m2. The lower dose was accompanied by lesser increases in LDL and transaminases. Thus, a prospective study excluding obese patients could establish that a 20-mg dose is efficacious and associated with a lower frequency of adverse events.
A number of therapies, including dronabinol, megestrol acetate,24,25 and rhGH,26-29 are approved for the treatment of HIV-associated wasting. Orexigenic agents, such as dronabinol and megestrol acetate, increase appetite but have not been shown to increase lean body mass. rhGH was approved for treatment of patients with HIV-associated wasting based on a trial that demonstrated increases in fat-free mass and increased performance on treadmill testing.28 rhGH is expensive, however, and its administration is associated with adverse effects at the approved doses. Oxandrolone compares favorably with rhGH in terms of the weight and BCM gain as well as retail cost. Furthermore, oxandrolone did not reduce fat stores and is associated with a lower frequency of adverse events than rhGH. Therefore, it may be viewed as an adjunct or alternative to rhGH for the treatment of patients with HIV-associated weight loss. Of 2 recent smaller studies on the use of nandrolone, an injectable anabolic steroid, for AIDS wasting, one reported that nandrolone induced a similar gain in weight67 to the increase seen here with oxandrolone, whereas the other found that nandrolone induced a larger gain in weight than we report with oxandrolone. Oxandrolone has the advantage of oral administration, however, which may be important in patients with loss of muscle and fat, such as occurs in AIDS wasting. Further studies are needed to determine the efficacy of oxandrolone in improving muscle strength, physical function, and health-related QOL in HIV-infected patients with weight loss.
Biotechnology General (now Savient Pharmaceuticals) provided the statistical analysis using the study's predetermined criteria and performed secondary analyses.
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The following individuals were participants in the Oxandrolone Study Group:
Victor Beer, MD, Beer Medical Group, 5901 West Olympic Boulevard, Suite 505, Los Angeles, CA 90036
Daniel Berger, MD, Center for Special Immunology, 2835 North Sheffield Avenue, Suite 104, Chicago, IL60657
Shalender Bhasin, MD, Charles R. Drew University of Medicine and Science, 1621 East 120th Street, MP-02, Los Angeles, CA 90059
Eric S. Daar, MD, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, B217, Los Angeles, CA 90048
Douglas Dieterich, MD, Liberty Medical, LLP, 345 East 37th Street, Suite 306, New York, NY 10016
Adrian S. Dobs, MD, Johns Hopkins University, Department of Endocrinology and Metabolism, Blalock 906, 600 North Wolfe Street; Baltimore, MD 21287-4904
Richard Elion, MD, Community Care Center, 1737 20th Street NW, Washington, DC 20009
Jeffrey Fessel, MD, Kaiser Permanente Medical Center, HIVResearch Unit, 4141 Geary Boulevard, Room 221, SanFrancisco, CA 94115
Marshall J. Glesby, MD, Community Research Initiative onAIDS, 230 West 38th Street, 17th Floor, New York, NY10018
Carl Grunfeld, MD, PhD, University of California at San Francisco, Metabolism Section (111F), and Department of Veterans Affairs Medical Center, 4150 Clement Street, San Francisco, CA 94121
Barbara Johnston, MD, St. Vincent's Hospital and Medical Center, 36 Seventh Avenue, Suite 415, New York, NY 10011
Donald Kotler, MD, St. Luke's-Roosevelt Hospital Center, Gastrointestinal Immunology S&R 1301, 1111 Amsterdam Avenue, New York, NY 10025.
Craig A. Lindquist, MD, PhD, Marin County Specialty Clinic, 161 Mitchell Boulevard, Suite 200, San Rafael, CA94903
Alvin E. Fisher, MD, Omega Medical Research, 400 Reservoir Avenue, Suite LL 1J, Providence, RI 02907
Jeff P. Nadler, MD, University of South Florida, Division ofInfectious Disease Center, 12901 North 30th Street, Box 19, Tampa, FL 33612
Dorece Norris, MD, Center for Quality Care, 508 SouthHabana Avenue, Suite 240, Tampa, FL 33609
Richard Pollard, MD, University of Texas Medical Branch atGalveston, 301 University Boulevard, Suite 722, Galveston, TX 77555-0882
Peter Shalit, MD, 600 Broadway, Suite 420, Seattle, WA 98122
Daniel Skiest, MD, University of Texas Southwestern Medi-cal Center at Dallas, Division of InfectiousDiseases, 5323 Harry Hines Boulevard, Dallas, TX75235
Paul Skolnik, MD, Division of Geographic Medicine and Infectious Diseases, New England Medical Center, 750 Washington Street, NEMC 67, Boston, MA02111
James Sosman, MD, HIV Program, University of Wisconsin, J5/215 CSC, 600 Highland Avenue, Madison, WI 53792
Corklin Steinhart, MD, Special Immunology Services/Mercy Hospital, Steinhart Medical Group, 3569 South Miami Avenue, Suite 4006, Miami, FL 33133
James H. Von Roenn, MD, Northwestern University, Hematology/Oncology Division, 233 East Erie, Suite 700, Chicago, IL 60611
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