AEGiS-GMHC: Inhibiting TNF to Preserve Lean Body Mass

Important note: Information in this article was accurate in 1995. The state of the art may have changed since the publication date.

Inhibiting TNF to Preserve Lean Body Mass

Treatment Issues; Vol. 9, No. 5 - May 1995
Theo Smart

A few years ago, tumor necrosis factor alpha (TNF) was administered to people with AIDS. In one study, HIV-positive patients with Kaposi's sarcoma were treated with TNF. All the patients experienced significant side effects, and their KS lesions grew -- one participant died during the study.1 Researchers now suspect that TNF plays a role in a whole host of AIDS-related complications, including neurologic problems, bone marrow suppression, the growth of KS lesions, and perhaps most importantly, AIDS-related wasting (loss of lean tissue).

TNF is a cytokine produced by circulating white blood cells called monocytes in response to infection. The cells of the immune system produce a wide variety of cytokines with differing effects on immune function. These cytokines have effects on body metabolism that parallel their role in the immune response. The observed metabolic effects of chronic exposure to TNF include fever, anorexia, hypermetabolism and, finally, wasting. TNF furthermore can trigger the release of a cascade of other factors implicated in wasting and other symptoms, among them such cytokines as interleukin-1, endocrine hormones, prostaglandin E2 and the leukotreines.2,3 TNF has also been shown to activate latent HIV infection within cells.4

The list of therapies promoted as TNF reducers is quite long and, besides thalidomide (see page 4), includes: pentoxifylline (Trental), ketotifen (see page 7), tenidap (an anti-arthritis medication), vesnarinone, cyclosporine, peptide T, sulfasalazine, Thorazine, many antioxidants, corticosteroids, anti-TNF monoclonal antibodies, recombinant TNF soluble receptors, marijuana (see box, page 8), glycyrrhizin, sho-saiko-to (SSKT, a Chinese herbal formulation), L-carnitine, hyperthermia and hyperbaric oxygen therapy.

Most of these therapies have been reported to reduce TNF in the test tube. It is hard to tell whether a drug achieves this in the body -- there are conflicting reports about several of the therapies mentioned above. Even when there is a broad consensus that a given disease elevates TNF, there is always a study or two that contradicts that conclusion. These discrepancies could be due to a number of factors. First, TNF has a very short half life, and if blood samples aren't tested right away, assays probably will not detect it. Second, TNF quickly binds to soluble and cellular receptors (which makes it undetectable in many tests), but this doesn't mean that it can't still do damage. There are several laboratory tests that measure TNF, both free and bound, but researchers do not agree on which to use.

Since one cannot rely on the highly variable data concerning TNF levels, a better way to evaluate drugs that reportedly lower TNF may be to look at their effects on other markers of immune and viral activity. Also, do such drugs have a clinical impact -- in particular, do they slow or reverse AIDS-related wasting?

Pentoxifylline, for example, seemed to have potential a year or so ago, but enthusiasm for this drug has waned. Most studies show that it does reduce TNF. Only one study has reported that it reduces HIV levels and then, only at one time point during the study. No clinical benefit has been noted. Although there are reports that pentoxifylline reversed wasting in a few cancer patients, this benefit has not been seen in people with AIDS. It remains to be seen whether other TNF inhibitors perform in a similar manner.

References

1 Kahn J et al. Journal of Acquired Immune Deficiency Syndromes. Mar 1989; 2(3):217-23.

2 Tracey KJ. In: Beutler B, ed. Tumor necrosis factors: the molecules and their emerging role in medicine. 1992; Raven Press, New York. pp. 237-254.

3 Rothwell NJ et al. Ibid. pp. 237-254.

4 Clouse KA et al. Journal of Immunology. Jul 1989; 143(2):470-475.

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