Tat Inhibitor Update

In our last issue (December 20), we listed the tat
inhibitors as the most important potential AIDS/HIV treatment at
this time, and said that Hoffmann-La Roche, which developed the
only tat inhibitor now in human trials, was expected to announce
that it had sold rights to the drug, code-named Ro-24-7429, to
another pharmaceutical company. Such an announcement had been
widely expected; but on December 19 (after our issue had gone to
press), Hoffmann-La Roche announced it had decided to keep the
drug and develop it itself. Apparently the company decided that
this drug was too good to sell -- especially in view of the
disappointing results with the competing class of non-nucleoside
reverse-transcriptase inhibitors (including Merck's L-661 and
Boehringer Ingelheim's BI-RG-587), which are not promising
because HIV develops resistance to them very rapidly.

As we reported in our December 20 issue, both theory and
data suggest that HIV may never develop resistance to tat
inhibitors. (A San Francisco newspaper report last week that L-
661 and BI-RG-587 are tat inhibitors was erroneous.)

On December 20, a technical article on Ro-5-3335 (a tat
inhibitor which is an earlier version of Ro-24-7429, but
apparently was abandoned because of toxicity in animal tests)
appeared in Science (MC Hsu and others, "Inhibition of HIV
Replication in Acute and Chronic Infections in Vitro by a Tat
Antagonist," pages 1799-1802). This article reports that the
experimental drug was effective against all of the many HIV
variants against which it was tested, and that it was equally
effective against AZT-resistant and AZT-susceptible viral
isolates. It did not include the key information, reported in
our last issue, that extensive attempts to develop a virus
resistant to Ro-5-3335 had failed to do so -- while the same
technique succeeds very easily in producing virus resistant to
L-661 and BI-RG-587.

The new Science article does note the concern about possible
toxicity of Ro-5-3335 -- reinforcing the important point that our
attention should be on the entire class of potential tat-
inhibitor drugs, not only on the one drug now in human trials.