Imuthiol: Confusion Continues

As our last issue went to press, we learned that Imuthiol (also called diethyldithiocarbamate, ditiocarb, or DTC) was being withdrawn by its sponsor, Institut Merieux of Lyon, France, after disappointing results from a preliminary analysis of a large clinical trial in France -- results suggesting that study participants did better on placebo than on the drug. No one knows why this study turned out so differently from the previous large, placebo-controlled trials.

The French study assigned 1600 volunteers to receive either Imuthiol or placebo. Most of the 1600 were asymptomatic, but a subset of 120 did have AIDS-related symptoms; the results for this subset were similar to those for the study as a whole. Spokesperson Sandy Kaufman of Connaught Laboratories, Inc., in Swiftwater, Pennsylvania -- a company recently acquired by Merieux and now acting as its representative in the United States -- gave us the following breakdown of disease-progression percentages during the two-year trial:


Imuthiol Placebo

Progression to ARC 24.7% 19.9%

Progression to AIDS 16.5% 10.3%

Opportunistic infections 10.7% 7.4%


It is hard to interpret these numbers without more information; they do, however, give a sense of proportion about the size of the difference this study found between treatment and placebo groups. These figures are preliminary, and will probably change somewhat when the data is analyzed further.

These results contrast with those of all previous placebo- controlled trials of Imuthiol. The largest of these earlier studies gave Imuthiol or placebo for six months to 389 symptomatic HIV-positive volunteers at medical centers in the United States.1 There were about twice as many AIDS-defining opportunistic infections in the placebo group as in those using Imuthiol; however, no survival benefit was seen with the drug.

Could Imuthiol be helpful during the first six months of treatment, but then do more harm than good later? Possibly -- but one physician, interviewed below, has seen good two-year results with Imuthiol combined with acyclovir. (The French study did not combine the drugs; for this and other reasons, the results are not directly comparable.)

Persons now using Imuthiol face what may be a difficult decision of whether to continue the treatment until more is known -- using Antabuse as a substitute, or possibly generic DTC, if Imuthiol becomes unavailable -- or to stop now. A meeting of Imuthiol researchers has been scheduled for September, but we do not know when a final report (or other new information) will become available.

For AIDS researchers and the community as a whole, it will be important to learn more about why major Imuthiol trials have produced such different results. One difference between the studies is that the earlier trials lasted six months, whereas the new one lasted two years. Six-month data from the recent French trial would be easy to tabulate, and it would answer critically important questions. If Imuthiol looked good at six months but bad at two years, there would be serious practical consequences for other drugs which might have a similar mechanism of action, since long-term trials would be required to test them. But if the new data from the French trial already looks bad at six months, then something other than the length of the trial must have caused the difference between the new study and the previous trials.

Some physicians and patients who have used Imuthiol believe it is too early to give up on the drug until more is known about why the study results have been contradictory.

References

1. Hersh EM, Brewton G, Abrams D, and others. Ditiocarb sodium (diethyldithiocarbamate) therapy in patients with symptomatic HIV infection and AIDS. A randomized, double- blind, placebo- controlled, multicenter study. JAMA, March 27, 1991; volume 265, number 12, pages 1538-1544.