This is a discussion of requests for information received by various drug information centers and is edited by the Drug Information Analysis Service at the University of California, San Francisco.

Published in The Annals of Pharmacotherapy, May, 1994, Volume 28)

Excerpts from this article address: the study on which FDA approval was given to use dronabinol for AIDS wasting, effectiveness of various other drugs on this condition, including: megestrol zidovudine therapy, and didanoside. Nutritional guidelines are also included in this article. (In calculating weight gain, 1 kg equals 2.205 pounds.)

Request

What is the treatment for HIV wasting syndrome?

Response

"Wasting associated with HIV was recognized by the Centers for Disease Control (CDC) in September 1987 with the revised definition for AIDS. The HIV wasting syndrome is characterized by at least a 10 percent weight loss with chronic fever, weakness, or diarrhea in the absence of other related illnesses contributing to the weight loss. The detection of these symptoms with concurrent presence of HIV antibody is sufficient to make the diagnosis of AIDS."

"Although the HIV wasting syndrome has often been equated with wasting induced by other chronic diseases, significant differences exist. For example, HIV-related wasting progresses more rapidly than wasting related to cancer. Moreover, HIV-related weight loss commonly approaches 20 percent of normal body weight in contrast to the 10 percent weight loss found in other chronic diseases, such as cancer and tuberculosis. Many treatments for HIV-related wasting have been proposed, based on data collected from studies of wasting induced by other chronic diseases. However, there is a lack of supporting data for efficacy specific to AIDS patients."

"Treatment strategies for the HIV wasting syndrome have been devised based on the proposed mechanisms. Overall nutritional status should be assessed and education provided to patients regarding proper dietary intake, as defined by the Task Force on Nutrition in AIDS in the Guidelines for Nutrition Support in AIDS. Decreased nutritional intake may be reversed with appetite stimulants such as dronabinol and megestrol. Nutritional malabsorption can be alleviated with enteral or pareneteral nutrition. Metabolic disturbances are related to the infectious process of the disease; therefore, appropriate treatment of the underlying infection using antiretroviral agents such as zidovudine or didanosine, or specific antimicrobial agents, may slow the progression of HIV-related wasting."

"The FDA approved the use of dronabinol for anorexia in AIDS patients on December 22, 1992, five months after the supplemental new drug application was filed. The recommended dosage is 2.5 mg twice a day, before lunch and before dinner. The request for the new indication was based on results from a randomized, double-blind, placebo-controlled clinical trial involving 139 AIDS patients in 18 centers. Patients with a 2.3-kg weight loss, no active infection and no marijuana use for 30 days were included in the study. Dronabinol 2.5 mg was administered orally twice a day to the treatment group. Results from a visual analog scale indicated a statistically significant (p<0.05) increase of appetite in patients treated with dronabinol after six weeks of therapy. However, the 0.1-kg average weight gain in treated patients was not significantly different from the 0.4-kg average weight loss in the placebo group at the end of the six week period (p>0.05). The efficacy of dronabinol in reversing the wasting process in AIDS patients is yet to be determined, since increased appetite does not necessarily correspond to increased body cell mass."

(Megestrol)

"In a pilot study performed by VonRoennen et al.. 22 HIV-positive patients experiencing severe anorexia and weight loss were treated orally with megestrol acetate 80 mg four times daily. Patients were evaluated week for the first month, then monthly thereafter for changes in weight and appetite and for evidence of adverse drug reactions. The daily dose was increased by 140-mg increments after 12 weeks of therapy if there had been no increase in weight. Four patients died of recurrent opportunistic infections, but all four continued to gain weight until their last hospitalized day. Weight gain averaged 7.3 kg (range -4.1 to 17.3) with peak effects occurring at a median of 14 weeks. Patients were monitored specifically for the anticipated adverse effects of glucocorticoids, such as peripheral edema, sexual dysfunction, and evidence of thromboembolic disease. The only adverse effect detected was deep venous thrombosis in one patient. Improved appetite was noted in 21 patients. The study lacked measurement of body cell mass, which would prove more useful in differentiating between increased body cell mass and body fat mass."

"Two 12-week controlled trials, involving 369 AIDS patients who lost 13.6 kg. demonstrated that patients treated with megestrol 400 or 800 mg had a weight increase of .3 - 3.2 kg versus a loss of 0.9 kg in placebo groups. However, there were 20 deaths (7 percent) among 283 treated patients compared with two deaths (2 percent) in 86 control patients. The difference in mortality rate was not statistically significant, but a trend toward an increased mortality rate was noted among patients treated with megestrol."

(Food Guidelines:)

"Specific guidelines have been set by nutritionists for the proper formula for enteral nutrition in AIDS patients. Low-molecular-weight proteins of less than 500 Da should be used in the form of free amino acids or polypeptides to minimize the need for digestion and ensure better absorption in the gastrointestinal tract. Glutamine and branched-chain amino acids are preferred for energy by the small intestine. Fat content should be minimized to less than 3 percent of the total caloric intake because of potential complications arising from malabsorption or diarrhea. Supplemental vitamins, minerals, and trace metals (including selenium and copper) should also be included. The enteral formula should be lactose free to minimize the risk of complications form lactose intolerance. The normal caloric and protein requirements for AIDS patients are in excess of those of the general population. An average person needs 30-35 kCal/kg/day and 0.8 - 1.5 of protein/kg/day, whereas an AIDS patients requires 35- 40 kCal/kg/day and 2.0 - 2.5 g of protein/kg/day. When indicated, enteral nutrition should be provided to patients with the HIV wasting syndrome in the proper amount and content to reflect the increased protein - energy needs in this population."

(Zidovudine therapy)

"A six-week study performed by Yarchoan et al. Randomized 19 patients with AIDS or AIDS-related complex (ARC), with or without weight loss, into four treatment groups. Zidovudine therapy was initiated at 1-5 mg/kg every 4-8 hours intravenously for two weeks, followed by twice the initial dose given orally for the remaining four weeks. Patients gained an average of 2.2 kg irrespective of dose. The weight gain was associated with increased appetite and waist size rather than fluid retention. A general sense of well-being was noted by six patients. No other measurements of body mass were performed. Reported adverse effects of zidovudine include headaches (47 percent), abdominal discomfort (5 percent), and leukocytopenia (11 percent); none required discontinuation of therapy."

(Didanoside Therapy)

"Lambert et al. published results from a Phase 1 trial in which 37 patients with AIDS or ARC were treated with escalating doses of didanoside. Treatment lasted for 2-44 weeks, with dosages ranging from 0.4 to 66 mg/kg/day. Two or more kilograms were gained by half of the patients. Major dose-limiting toxicities included peripheral neuropathy (21 percent) and pancreatitis (14 percent). Other adverse effects such as increased serum aminotransferase concentrations (35 percent) and serum urate concentrations (27 percent) were also reported."

(Dronabinol and Megestrol)

"Both dronabinol and megestrol have been shown to be effective in stimulating appetite with few adverse effects. A major weakness in the dronabinol studies is the lack of anthropometric or TBK measurements to assess the impact of treatment on body cell mass, which cannot be inferred from an increase in weight alone. Moreover, prolonged (>6 wk) dronabinol treatment may be necessary before weight gain can be observed. On the other hand, studies have shown megestrol therapy to be effective for weight gain in male AIDS patients, even in the presence of opportunistic infections. However, safety and efficacy may not be assumed in female patients."