TreatmentUpdate40: February 1993
Sean Hosein

RESULTS FROM THE USA - PHASE I

In one American study, called ACTG 160, 25 HIV-infected subjects were enrolled. All subjects had less than 300 CD4+ cells. The drug was given in a dose of 400 mg three times daily. During the study 2 subjects did not take the drug as directed and along with 6 other subjects withdrew from the trial. The 17 remaining subjects took the drug for 8 weeks. Compared with pre-study values, subjects with high levels of TNF given pentoxifylline had reduced levels of TNF. Subjects with high levels of triglycerides (triglycerides are used to build fats) at the start of the trial had them decline by the eighth week of the study. Production of HIV appeared to be reduced and weight loss may not have occurred as rapidly as before when subjects were not receiving pentoxifylline. According to the investigators, pentoxifylline appeared to be "safe" when tested in these subjects.

RESULTS FROM THE USA PHASE II

Given those encouraging results the researchers decided to use even higher doses of pentoxifylline, 800 mg twice daily for their next series of experiments on people with HIV infection. At last year's International AIDS Conference in Amsterdam where these results were presented, a Montreal-based doctor in the audience warned the Americans that reducing TNF to very low levels with high-dose pentoxifylline may be dangerous. The doctors associated with ACTG 160 did not comment on his warning.

RESULTS FROM THE USA NO 8ENEFIT

Other researchers in New York have reported less favourable results. Doctors there enrolled 5 subjects who had CD4+ counts of less than 201 cells and "AIDS-related wasting" into a study to assess the effect of pentoxifylline.

Subjects did not have diarrhea and were given "nutritional support" with products such as Ensure and Sustical. As well, subjects were taking AZT and/or ddI during the trial. Pentoxifylline, 400 mg three times daily, was used. Three subjects with high levels of TNF had them reduced while on the study. None of these subjects, however, experienced any improvement in their symptoms. In 2 other subjects with low pre-study levels of TNF weight loss continued. Both of these subjects developed serious bacterial pneumonia and one died as a result. According to the study investigators, pentoxifylline was of "no clinical benefit".

RESULTS FROM MONTREAL

These results are not surprising. One physician in Montreal (personal communicahon, Emil Toma, MD, data on file at CATIE) reported on his compassionate use of pentoxifylline in 18 HIV-infected subjects. Using doses of 400 mg twice daily, he found that the drug was "welltolerated." Any minor benefit he saw in his subjects was not sustained. Most subjects experienced worsening immunodeficiency despite use of pentoxifylline and continued anti-HIV therapy (AZT and/or ddI).

IS PENTOXIFYLLINE DANGEROUS?

A certain minimal level of TNF is needed by the immune system to defend against bacteria, fungi, viruses and tumours. Use of high-dose pentoxifylline may decrease blood levels of TNF below a critical level perhaps placing people at high risk for further infections. TNF has been shown to be useful when the immune system is attempting to contain infections caused by P. carinii (the cause of PCP) and T. gondii (the cause of toxoplasmosis). In some laboratory experiments, pentoxifylline appears to have immunosuppressive effects. In a situation of immune deficiency, high doses of pentoxifylline may make patients more susceptible to infections.

REFERENCES:

1. Dezube BJ, Pardee AB, Chapman B, et al. Pentoxifylline (Trental) decreases Tumour necrosis factor (lNF) and HIV replication in patients with AIDS. MOB 0019 In: Vlll Internationnl Conference on AIDS, Amsterdam, the Netherlands, July 19-24,1992. Amsterdam: Congrex Holland, 1992:MoB 0019.

2.Langermans JAM, VanDerHulst MEB, Nibbering PH and Van Furth R. Endogenous tumour necrosis factor alpha is required for enhanced antimicrobial activity against Toxoplasma gondii and Listeria monocytogenes in recombinant gamma interferon treated mice. Infection and Immunity 1992;60(12):5107-5112.

3. Landman D, Sarai A, and Sathe S. Pentoxifylline-induced suppression of tumour necrosis factor in the treatment of AIDSrelated wasting (abstract 568). In: Program and abstracts of the 32nd Interscience Conference on Antimicrobial Agents and Chemotherapy (Anaheim). Washington, DC:American Society for Microbiology, 1992:205.

4. Reed WR and Gowin RL. Suppressive effects of pen~oxifylline on nanlral killer cell activity. Journal of Laboratory and Clinical Medicine 1992;119(6):763-771.

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Copyright © 1993 - TreatmentUpdate. Reproduced with permission. Reproduction of this article (other than one copy for personal reference) must be cleared through the Editor, The Canadian AIDS Treatment Information Exchange, 555 Richmond St. West, Suite 505, Box 1104, Toronto, ON, M5V 3B1 • Phone: 416-203-7122 • Toll Free: 1-800-263-1638 • Fax: 416-203-8284  http://www.catie.ca