AIDS TREATMENT NEWS Issue #306, November 6, 1998
John S. James

* At the highest dose tested, patients treated with T-20 alone had a viral load drop of 1.96 logs in 14 days. Analysis of viral dynamics shows that the drop was limited to two logs because the trial only lasted 14 days (since it takes the body that long to clear 99 percent of HIV from the blood, even if new production is completely shut off).

* All four patients at the highest dose of T-20 had remarkably similar viral decay dynamics--which appeared to be better than those observed in other trials with triple-drug HAART therapy, and almost as good as a trial of four-drug HAART therapy with treatment-naive patients. (Three of the four in the T-20 trial were treatment naive; the fourth had been treated but had been off other antiretroviral therapy for at least 14 days.)

* None of the 16 volunteers had to be taken off T-20 because of adverse effects or toxicity. A few had possible side effects such as fever or headache, but these did not appear to be drug related.

Comment

This trial was first reported over a year ago (September 16), at the IDSA (Infectious Diseases Society of America) meeting in San Francisco3; we summarized that presentation in AIDS TREATMENT NEWS issue #279, September 19, 1997. Unfortunately that report received little public attention, for several reasons. The technical details have not been published until now; the drug's mechanism of action is new and difficult to understand; the sponsoring company (Trimeris, Inc., in Durham, North Carolina) was in a "quiet period" at the time of the conference and could not publicize the results; and there were very few treatment activists at that particular conference.

In this trial T-20 was administered intravenously twice a day. It is likely that the drug can be administered more efficiently subcutaneously, by a portable computerized infusion pump, like the pump widely used in diabetes treatment to administer insulin.

This study has clearly established proof of principle for a drug with an entirely new mechanism of action (which means, among other benefits, that no cross-resistance is expected between T-20 and any treatment now in use). Viral resistance to T-20 does occur; it is not known how much problem it will cause in practice. It is possible that resistance might be managed by using T-20 to shut off viral replication almost completely--since blood levels can be much higher than necessary to prevent replication, and the infusion pump eliminates food, absorption, and peak-trough issues, and should greatly improve adherence. Other possible approaches for managing resistance include combining T-20 with other antiretrovirals, or creating a new version of T-20 to target the resistant virus.

A new trial, TRI-003, is currently recruiting and about half filled as we go to press (see AIDS TREATMENT NEWS #300, August 7, 1998). It will obtain longer-term viral suppression data, and verify dosage for the infusion pump. It will also check to see if the body produces antibodies against T-20-- which might or might not be a problem in long-term use.

Currently T-20 is difficult to produce in large quantities. But there is little doubt that efficient manufacturing methods can be developed.

References

1. Kilby JM, Hopkins S, Venetta TM, and others. Potent suppression of HIV-1 replication in humans by T-20, a peptide inhibitor of gp41-mediated virus entry. NATURE MEDICINE. November 1998; volume 4, number 11, pages 1302-1307.

2. Richman DD. Nailing down another HIV target. NATURE MEDICINE. November 1998; volume 4, number 11, pages 1232- 1233.

3. Saag M, Alldredge L, Kilby M and others. A short-term assessment of the safety, pharmacokinetics, and antiviral activity of T-20, an inhibitor of gp41 mediated membrane fusion. IDSA 35th Annual Meeting, San Francisco, September 16, 1997 [abstract #771].
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