The Effect of Thalidomide on the Pathogenesis of Human Immunodeficiency Virus Type 1 and M. tuberculosis Infection

Abstract

Tumor necrosis factor alpha (TNF-alpha), a cytokine produced during the host defense against infection, is associated with fevers, weakness, and progressive weight loss. Thalidomide inhibits the synthesis of TNF-alpha both in vitro and in vivo and may have clinical usefulness. We therefore initiated a pilot study of thalidomide treatment in patients with human immunodeficiency virus type 1 (HIV-1)-associated wasting with or without concomitant infection with tuberculosis. Thirty-nine patients were randomly allocated to treatment with either thalidomide or placebo in a double-blind manner for 21 days. Thirty-two patients completed the study. In patients with concomitant HIV-1 and tuberculosis infections, thalidomide therapy was associated with a reduction in both plasma TNF-alpha levels and HIV-1 levels. No significant reduction in either TNF-alpha or HIV- 1 levels was observed in patients with HIV-1 infection only. During the study period, patients receiving thalidomide treatment (n=16) showed a significant weight gain (mean +/- SEM: 6.5 +/- 1.2%; p<0.02) relative to placebo-treated patients (n=16). Patients with simultaneous HIV-1 and tuberculosis infections experienced a higher mean weight gain during thalidomide treatment than the group of patients with HIV-1 infection only. The results of this pilot study suggest that thalidomide may have a clinical role in enhancing weight gain and possibly reducing TNF-alpha and HIV-1 levels in patients with HIV-1 and concomitant mycobacterial infections.

Tumor necrosis factor alpha (TNFalpha) promotes growth of virulent Mycobacterium tuberculosis in human monocytes iron-mediated growth suppression is correlated with decreased release of TNFalpha from iron-treated infected monocytes.

“…This result has particular relevance to disease caused by these pathogens since they often coexist, and, individually, both HIV 1 disease and mycobacterial infection have been associated with elevated serum TNF␣ levels (49,50). A recent study using thalidomide, an inhibitor of TNF␣ production by mononuclear phagocytes (51), indicates that decreasing TNF␣ levels in patients with HIV 1 infection and tuberculosis is associated with a reversal of tuberculosis-induced weight loss, and a concomitant reduction in plasma HIV levels (52). Thus, blocking TNF␣ may have beneficial effects for both these disease states.…”

Phase I study to determine the safety, tolerability and immunostimulatory activity of thalidomide analogue CC-5013 in patients with metastatic malignant melanoma and other advanced cancers

“…Thalidomide has also been shown to be a useful drug in a wide range of other clinical conditions for which there is little other treatment option (Marriott et al, 1999;Raje and Anderson, 1999). These include rheumatoid arthritis (Schuler and Ehninger, 1995), the inflammatory and wasting effects of chronic tuberculosis (Klausner et al, 1996), Behcet's disease (Hamuryudan et al, 1998), Crohn's disease (Wettstein and Meagher, 1997;Ehrenpreis et al, 1999;Vasiliauskas et al, 1999) aphthous ulcers (Youle et al, 1989;Alexander and Wilcox, 1997;Jacobson et al, 1997), cachexia (wasting) associated with HIV infection (Sharpstone et al, 1995;Reyes-Teran et al, 1996) and AIDS-related Kaposi's sarcoma (Fife et al, 1998). There is also a wide body of evidence from large-scale clinical trials showing the effectiveness of thalidomide as a treatment for refractory or relapsed multiple myeloma (MM) (Singhal et al, 1999;Hideshima et al, 2000;Juliusson et al, 2000;Kneller et al, 2000;Zomas et al, 2000), and this extends to the treatment of a number of other tumours (Eisen et al, 2000;Fine et al, 2000;Gutheil and Finucane, 2000;Patt et al, 2000;Tseng et al, 2001;Eisen, 2002).…”

A Single Oral Dose of Thalidomide Enhances the Capacity of Lymphocytes to Secrete Gamma Interferon in Healthy Humans

“…The clinical symptoms of patients with Mycobacterium avium infections refractory to conventional treatment improved dramatically with thalidomide treatment (3,11). In patients with concomitant HIV and Mycobacterium tuberculosis infection, thalidomide increased the weights of patients significantly, while their HIV loads decreased (16). Thalidomide has also been found to be beneficial in a variety of other diseases, including aphthous ulcers, Behçet syndrome, erythema nodosum leprosum (ENL), and microsporidiosis (13,15,26,28).…”