Treatment
Megestrol acetate (Megace®) oral suspension has been approved by the FDA for the treatment of anorexia, cachexia, or unexplained significant weight loss in patients with AIDS. The recommended dose is 800 mg/day. This approval was based on data from two, twelve-week, placebo-controlled studies conducted in patients with AIDS-related wasting.
Von Roenn et al. have reported results of megestrol acetate in a 12-week placebo controlled trial in 271 patients. A total of 270 patients were evaluable for safety data and 195 patients were evaluable for efficary data. AIDS patients were randomized to receive placebo or megestrol acetate (100 mg, 400 mg, or 800 mg qd). Of the 195 evaluable patients, 64.2% gained 2.27 kg (5 lbs) or more compared with 21.4% of patients in the placebo group (P < 0.001). The most significant weight gain reported was in the 800 mg megestol acetate group (n = 75) when compared to placebo; 62.3% reporting a median weight gain of 3.54 kg (7.8lbs) at l2weeks (P <0.001). Lean body mass were also reported using bioelectrical impedence analysis. The mean change in lean body mass from baseline to last evaluation was 1.14 (2.5 lbs) in the 800 mg megestrol acetate group and -0.14 kg (-O.03 lbs) in the placebo group (P < 0.001).
Results from a 12 week, randomized, placebo-controlled study of 100 patients with AIDS-related weight loss of 10% or more of ideal body weight were reported by Oster et al. 52 patients received megestrol acetate and 48 received placebo. Body weight in the magestrol acetate group increased by 3.86 kg from baseline to week 8 (P < .001), while body weight decreased in the placebo group 0.46 kg. Body water, lean body mass, and patient survival were not statisticauy different between the two groups.
To deterinine whether fat mass associated with megestrol acetate administration is caused by the hypogonadic effects of the drug, resulting in lower testosterone production in men, the AIDS Clinical Trials (ACTG) is currently desiging a study to test thishypothesis. ACTG 610 will enroll patients with greater than 5% loss in body weight to receive megestrol acetate with or without testosterone.
Dronabinol has been approved as an appetite stimulant in AIDS patients with wasting. Side effects associated with dronabinol include dizziness, thinking abnormalities, asthenia and euphoria. Beal et al. enrolled 139 AIDS patients in a double-blind, placebo-controlled trial. All patients were at least 2.3 kg below their ideal body weights and were free from intercurrent illness. Patients were randomized to receive dronabinol 2.5 mg bid or placebo for six weeks, at which time all patients received dronabinol in an open-label extension of the study. After the randoniized study, 5O/72 dronabinol recipients and 38/67 placebo recipients were evaluable. Appetite (measured on a visual analog scale) was significantly iinproved in the dronabinol group (P = 0.02). Mean weight change was 0.1 kg in the dronabinol group and -0.4 kg in the placebo group (P = NS). At the end of the first month of the open-label extension study, 7/18 patients who had originally received dronabinol had gained 2 kg, compared to 2/17 patients who had originally received placebo (P = 0.07). Although CNS side effects were conimon in the dronabinol group, adverse reactions requiring discontinuation of therapy were equally frequent in the two groups (5 on dronabinoi and 4 on placebo).
A New Drug Application has been submitted by the manufacturer of recombinant human growth hormone (rHGH). Recombinant Human Growth Hormone is the first anabolic agent shown in clinical trials to increase lean body mass and body weight in people with AIDS-related wasting syndrome.
Results from a 12-week, multicenter, placebo-controlled trial of recombinant human growth hormone [rHGH (average dose of 6 mg daily)] in 178 patients with AIDS-associated weight loss was presented by Schambelan et al. Patients enrolled in the trial had lost an average of 14% of their normal body weight. Ninety patients were randomized to rHGH 0.l mg/kg qd; 88 patients received placebo. A median weight gain of 1.6 kg was reported in patients receiving rHGH (P = 0.01). A median lean body mass increase of 3.0 kg was also reported (P < 0.001), accompanied by a median decrease of 1.7 kg in fat mass (P < 0.001). There were five deaths among the participants; three were receiving the hormone and two were on placebo. No significant differences in the development of opportunistic infections or survival were reported.
Results from a second 12-week, multicenter, placebo-controlled trial of recombinant human growth hormone (rHGH) has been reported (Kaufmann et al.). A total of 177 patients were randomized to receive rHGH or placebo for 12 weeks; 115 patients received rHOH (average dose of 6 mg daily) and 62 received placebo. At baseline, patients had lost an average 10.5 kg of their ideal body weight. Lean body mass and fat mass parameters were not measured. At 6 weeks, the median, weight gain in the placebo group was 2.5 kg above baseline, whereas the median weight gain in the placebo group was.7 kg (P < 0.001). At week 12, the median weight gain decreased to 1.6 kg above baseline in the rHOH group and increased to 4.3 kg in the placebo group. Data at week 12 were not statistically significant. There was not significant difference in the development of opportunistic infections or death in either group (3 deaths in total).
Mulligan et al. treated six men with HIV-related weight loss (mean loss of 19%) with a constant metabolic diet and rHGH 0.1 mg/kg/day for seven days. The men were hospitalized, as were six HIV-negative volunteers who served as controls. A mean body weight increase of 2.0 + 0.3 kg was observed in the HIV-posifive men (compared with 1.6 + 0.2 kg increase in the control group). Increases in protein anabolism and lipid oxidation were observed.
Landman et al. treated five patients with AIDS-related wasting with pentoxifylline 400 mg three tlmes daily. The rationale for the treatment was based on pentoxifylline's anti-TNF-activity; TNF may play a role in the pathogenesis of AIDS wasting. 3/5 patients had elevated serum TNF-levels. No significant weight gain was observed in any of the patients. In the two patients without elev]ated TNF, they continued to lose weight and also developed bacterial pneumonia within 3 weeks of starting therapy.
Thalidomide is being investigated as a possible treatment for AIDS-related wasting, due to its anti-TNF-actvity. In a study presented by Reyes-Teran et al., 23 patients receivmg antiretroviral therapy, without active opportunistic infections, and with 10% or or greater weight loss in the previous six months were included into a randoniized, double-bhnd, placebo-controlled efficacy trial. 18 patients have finished the treatment protocol. Stabalization or weight gain occurred in 8/9 patients from the thalidomide group and in 2/9 from the placebo group (P = 0.008). Mild and transient somnolence and erythematous macular lesions were only observed in the thalidomide group.
A randomized, placebo-controlled study of thalidomide for the treatment of wasting syndrome is currently underway. For patients who do not qualify for the randomized trial, an expanded access program has been set up by the manufacturer.
Two studies are currently underway of testosterone transdermal (scrotal) system.
The first is a multicenter study examining testosterone transdermal system as a treatment for hypogonadism in HIV-positive patients; the second is a small study examining testosterone replacement as a treatment for wasting. A study of testosterone IM versus a testosterone transdermal system is being conducted by the Community Research Consortium of the University of Califomia/San Francisco.
Some anecdotal reports have suggested that anabolic steroids may have a role in the treatment of AIDS-related weight loss (Jekot and Purdy). However, data from controlled clinical trials in AIDS patients hae been limited.
Oxandrolone, an anabolic agent which has been approved by the FDA for treatment of weight loss associated chronic illness, is being studied in a multicenter, randomized, double-blind, placebo-controlled trial.
A recent study completed by Hengge et al. of oxymethalone in combination with ketotifen has been completed. A total of 30 patients were treated in an open-label fashion and were divided evenly to receive either oxymethalone monotherapy or a combination of oxymethalone and ketotifen. A group of 30 matching controls were also evaluated. No additive benefit of ketotifen was reported. The mean body weight increase between the two groups was 7/15 kg at approximately 20 weeks of therapy.
NIH is currently developing a clinical trial (CS 610) to study the effects of nandrolone, an anabolic steroid, in HIV-positive women with greater than 5% loss in body weight.
REFERENCES:
Couderc LJ et al. Thalidomide in wasting syndrome in AIDS. Abstract P 321, Fourth European Conference on Clinical Aspects and Treatment of HIV Infection. Milan, 1994.
Hengge UR et al. Oxymethalone promotes significant weight gain in patients with advanced HIV-1 infection. Abstract #394. 3rd Conf on Human Retro and Opport Infect, Washington DC, 1996.
Jekot WF and Purdy DW. Treating HIV/AIDS patients with anabolic steroids. A retrospective study. AIDS Pat Care, 68-74, April, 1993.
Kaufmann B et al. Data from the Metabolic and Endocrinology/Antiviral Advisory Committee of the Food and Drug Administration's approval hearing for recombinant humm growth hormone. Silver Spring, MD, 1996.
Landman D et al. Use of pentoxifylline therapy for patients with AIDS-relatcd wasting: pilot study. Clin Inf Disease 18:97-9, 1994.
Mulligm CK et al. Anabolic effecls of recombinant human growth hormone in patients with wasting associated with human immunodeficiency virus infection.
J Clin Endo Metab 77:956-62, 1993.
Oster et al. Megestrol acetate in patients with AIDS and cachexia. Ann Int Med 121:400-408, 1994.
Von Roenn J et al. Megestrol acetate in patiets with AIDS-related cachexia. Ann Int Med 121: 393-99, 1994.
Reyes-Teran G et al. Effects of thalidomide on wasting syndrome in patients with AIDS, a randomized, double-blind, placebo-controlled trial. Abstract #563B, X Intl Conf AIDS, Yokahama, 1994
Schambelan M et al. Recombinant human growth harmone increases lean body mass and improves functional performance in patients with HIV-associated wasting. 2nd Human Retrovirus Conference, Abstract #LB-15, Washington DC, 1995.
OTHER REPORTS:
Grunfeld C et al. Metabolic disturbances and wasting in the acquired immunodeficiency syndrome. NEJM 327,:329-37, 1992.
Hickey M et al. Nutritional management of patients with ARC or AIDS.
Gastro Cl N Amer 17: 546-61, 1988.
Kotler D et al. Malnutrition in HIV infection and AIDS. AIDS 3(supp-1): 175-90, 1989.
Kotler D et al. A randomized, double blind, placebo-controued Phase II trial of growth hormone and insulin-like growth factor-I for AIDS wasting. Abstract #110, ICAAC, Orlando, 1994.
Beal JE et al. Dronabinol as a treatment for anorexia associated with weight loss in patients with AIDS. J Pain Symptom Manage 10(2): 89-97, 1995.
Graham KK et al. Steady-state pharmacokinetic and pharmacodynamic evaluation of megestrol acetate oral suspension in cachectic AIDS patients. 31st ICAAC, Abstract 550, 1991.
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