Published in the Bulletin of Experimental Treatments for AIDS January 1999 issue, by the San Francisco AIDS Foundation.

January 1999 Table of Contents

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DRUG WATCH: T-20 -- First of a New Class of Anti-HIV Drugs

Leslie Hanna

T-20 (also known as pentafuside, previously DP-178) is a powerful new experimental antiretroviral, and the most prominent of a new class of anti-HIV drugs, the fusion inhibitors. In vitro studies previously suggested that the drug had extremely potent antiviral activity; now, final results of a pilot study (reviewed below) in 16 people show that T-20 can reduce plasma HIV viral load by two logs. T-20 is manufactured by Trimeris, Inc, of Durham, NC.

A Novel Mechanism of Action

T-20 is a synthetic 36-amino acid peptide. As a fusion inhibitor, T-20 attacks HIV at a point in its replication cycle not yet targeted by any existing antiretroviral. The drug targets the fusion phase of HIV infection, in which the HIV virion (virus particle) fuses or binds with a new target cell, such as a CD4 T-cell. T-20 is thought to somehow interfere with the gp41 surface molecule on HIV to the extent that the virus is incapable of binding with and thereby infecting new target cells.

In laboratory studies, T-20 was found to be a much more potent inhibitor of HIV-1 than HIV-2 (estimates range from 10 to 1,000 times greater HIV-1-specific potency). Like HIV-1, HIV-2 is a retrovirus believed to be a primary causal agent of AIDS; whereas HIV-1 is believed to cause AIDS in most of the world, HIV-2 is found primarily in West Africa.

In its current form, T-20 must be administered twice daily by intravenous injections or continuously by subcutaneous (under the skin) infusion. Researchers are working to develop a portable computerized infusion pump, similar to the pump used by diabetics to administer insulin. The pump, which has been compared in size to a pager, administers the drug slowly, constantly, and efficiently.

Clinical Trial Results

Results of the largest human trial of T-20 to date were published in the November 2, 1998 issue of Nature Medicine. (Preliminary results were reported previously at the September 1997 meeting of the Infectious Diseases Society of America -- see BETA, January 1998.) Conducted through the University of Alabama at Birmingham by Michael Kilby, MD, and colleagues, the trial lasted 14 days. Participants’ median CD4 cell count was 212 cells/mm³ and their median viral load was 58,884 copies/mL. The 16 participants were randomized into four groups of four persons each to take 3, 10, 30, or 100 mg of T-20 twice daily as monotherapy.

People who took the highest dose, 100 mg twice daily, experienced the largest reductions in HIV viral load. Within 10-14 days after beginning T-20, all four developed undetectable HIV levels, or a viral load drop of nearly two logs. Of these four, three were treatment-naive; that is, they had never before taken any antiretroviral therapy. The fourth had gone through a two-week washout period during which all therapy was stopped.

Results of this trial indicate that T-20 is well-tolerated overall. No one discontinued because of adverse events and no safety problems were reported. Although a few people reported fever and headache, investigators considered these unrelated to treatment.

Whether this highly potent antiretroviral will look as promising over the long term remains to be seen. As Douglas Richman, MD, wrote in an editorial in Nature Medicine, "HIV is chronic -- so too must be its treatment." Future studies will have to evaluate the drug’s ability to suppress HIV over a longer period of time, long-term tolerance, and toxicity. Another issue is adherence, which tends to be more difficult with chronic use of injected drugs.

Viral resistance to T-20 has not yet been seen. However, the longer any individual uses any given drug, the more likely it is that resistance to that drug will develop. Longitudinal data have not yet been reported on T-20. If used for extended periods of time, T-20 will be taken in combination with other antiretroviral drugs to delay the development of resistance. Since the drug has a new mechanism of action, it is unlikely to pose any problems with cross-resistance with other available antiretrovirals.

More Trials Underway

TRI-003, sponsored by Trimeris, is currently enrolling participants. This trial is designed to evaluate antiviral suppression over a longer period of time, and to establish the best dose of T-20 for use with the infusion pump. Researchers also will evaluate whether or not the body produces antibodies against T-20.

In San Francisco, there are two local study sites (Quest Clinical Research and San Francisco General Hospital). The 003 trial is fully enrolled at both sites, and plans for a third study are underway. Check Quest’s website at www.questclinical.com for updates on ongoing and upcoming T-20 trials. San Francisco General Hospital plans to begin enrolling for another T-20 study in January 1999.

Other planned trials will evaluate the efficacy of the drug in people who have failed all other available treatments.

The Future of T-20

T-20, the first member of the highly anticipated new class of fusion inhibitor drugs, is well worth watching; so far the only drawback to this promising drug is the form of administration. Richman, while enthusiastic about T-20, also recommends the development of a small peptide that acts similarly to T-20 and would also disrupt HIV infection by interfering with the ability of the virus to bind with host cells. This smaller agent could potentially be formulated as an oral medication.

Leslie Hanna is Acting Editor of BETA.

References

Page last updated 15 January 1999

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