Megestrol acetate is a synthetic, orally active, progestational agent, used widely in the treatment of metastasic breast cancer. It has also been reported to stimulate appetite and weight gain in patients with advanced cancer or AIDS-related anorexia and/or cachexia [1,2]. In these groups of patients many adverse events potentially related to megestrol have been reported, including adrenal suppression, diabetes, impotence and thromboembolic phenomena [3-6]. Deep venous thrombosis (DVT) has also been associated with advanced HIV infection and with pulmonary tuberculosis. Some authors suggested the presence of potentially thrombogenic factors, such as acquired deficiencies of C and S proteins, the presence of antiphospholipid antibodies, high levels of fibrinogen and depressed antithrombin III levels [7-10]. The frequent coexistence of HIV infection, tuberculosis and megestrol treatment with the appearance of DVT makes the establishment of a cause-effect relationship difficult.
Our group has followed a cohort of 199 HIV-infected patients for 2 years, 25 of whom (12.6%) were treated with 320mg/day megestrol. DVT was observed in seven patients (3.5%), three women and four men, with a mean age (±SD) of 38±10 years. Venous thrombosis was localized in the popliteal vein in five patients and in the femoral vein in the remaining two. All patients were at Centers for Disease Control and Prevention stage C3, with an average CD4 lymphocyte count of 43±43×106 cells/l. At the moment of the DVT, four patients had been undergoing treatment with megestrol for a period of 98±68 days, and three had a concomitant diagnosis of tuberculosis infection.
In three patients free protein S was determined once anticoagulation therapy was completed and a deficit of 44, 32 and 20% was found (reference values 50-130%). Protein C and anticardiolipin antibodies were also tested in these three patients, and normal or undetectable values were observed, respectively.
Univariate analysis showed a significant association between DVT and megestrol treatment, tuberculosis infection, severe immunodepression (CD4 lymphocyte count <100×106 cells/l) and death during the 2 years of follow-up (Table 1). Multivariate logistic regression showed that megestrol and tuberculosis were independent variables for the appearance of DVT, with an odds ratio (OR) of 7.6 (95% confidence interval (CI)=1.5-39.4) and 5.6 (95% CI=1.0-31.4), respectively. Finally, the effect of megestrol on the appearance of thromboembolic phenomena was not confounded by the severity of the HIV infection: it was independent of mortality during follow-up (OR=8.0, 95% CI=1.4-44.5) and probably also of severe immunodepression (OR=4.4, 95% CI=0.8-24.0).
In conclusion, the appearance of DVT in HIV-infected patients seems to have a multifactorial aetiology and be independently related to megestrol treatment, the presence of tuberculosis infection and the severity of the HIV infection.
1. Von Roenn JH, Armstrong D, Kotler DP, et al
. Megestrol acetate in patients with AIDS-related cachexia. Ann Intern Med
2. Gebbia V, Testa A, Gebbia N. Prospective randomised trial of two dose levels of megestrol acetate in the management of anorexia-cachexia syndrome in patients with metastatic cancer. Br J Cancer
3. Fernandez C, Marín S, Lopez G, Carbayo C. Tromboflebitis por acetato de megestrol en pacientes con infección por el virus de inmunodeficiencia humana. Med Clin (Barc)
4. Stoffer SS, Krakauer, JC. Induction of adrenal suppression by megestrol acetate. Ann Intern Med
5. Thürlimann B, Castiglione M, Hsu Schmitz SF, et al
. Formestane versus megestrol acetate in postmenopausal breast cancer patients after failure of tamoxifen: a phase III prospective randomised cross over trial of second-line hormonal treatment (SAKK 20/90). Eur J Cancer
6. Von Roenn JH, Murphy RL, Wegener N. Megestrol acetate for treatment of anorexia and cachexia associated with human immunodeficiency virus infection. Semin Oncol
1990, 17 (Suppl. 9):13-16.
7. Robson SC, White NW, Aronson I, Woollgar R, Goodman H, Jacobs P. Acute-phase response and the hypercoagulable state in pulmonary tuberculosis. Br J Haematol
8. Feffer SE, Fox RL, Orsen MM, Harjai KJ, Glatt AE. Thrombotic tendencies and correlation with clinical status in patients infected with HIV. South Med J
9. Laing RB, Brettle RP, Leen CL. Venous thrombosis in HIV infection. Int J STDAIDS
10. Bissuel F, Berruyer M, Causse X, Dechavanne M, Trepo C. Acquired protein S deficiency: correlation with advanced disease in HIV 1 infected patients. J AIDS