The Bay Area Reporter - September 28, 1998
Matthew Sharp ACT UP Golden Gate Writers Pool

As in battle, the more targets that are hit, the more the enemy is weakened; the weaker the viral infection, the more likely it can be destroyed altogether. Unfortunately, current combination therapies to hit the virus in multiple targets are toxic, and require incredibly complex dosing regimens with up to 40 pills a day.

And although today's treatments include effective drugs that target the protease and reverse transcriptase enzymes, there is still a need for new ways to attack HIV because its amazing mutation capabilities weaken the current treatments - and in some cases make them useless. People with HIV need new drugs that attack the virus at a different point of its life cycle, either to add benefit to current therapies or, possibly, to be more effective as a monotherapy.

Robert Gallo, co-discoverer of HIV, sent a promising message to the Geneva World AIDS conference this summer when he spoke about new targets for drug delivery. One of the new targets he spoke about is fusion, the process where HIV attaches to a CD4 cell or t-cell. The process is complex, and if all the stages are not in place the virus cannot attach, invade, take over the cell, and replicate. A new drug called T-20 competes with this natural process, and stops invasion outside the cell that HIV attaches to. T-20 is identical to a part of the HIV gp 41 attachment arm crucial for fusion. In early studies, it has been shown to stop the fusion process in HIV.

While there are many questions to be answered with this new therapy and mode of action, there is hope that it may be a possibly more effective treatment than any of the 14 available anti-HIV drugs today. Because the mode of action is different than current therapies that are failing for many people, there shouldn't be fear of cross resistance.

Pager-sized pump

Virus levels drop very rapidly with T-20 according to one early study. Also, since the drug works outside of cells, it has been shown to have fewer side effects because it is not toxic to cells. Granted there is little information on toxicities in large numbers of patients, but theoretically with T-20, the side effects should be minimal. There is one important caveat: the drug has to be administered with a 24-hour pump or at least at regular intervals by subcutaneous injection. According to Trimeris, the company that makes the drug, injection is absolutely necessary to ensure proper drug delivery. The drug cannot be absorbed in the human gastro-intestinal tract through an oral form. So tests need to be done to see if a pump or regular injections will work.

The pager-sized pump worn outside the body allows T-20 to be administered slowly and constantly with a small needle under the skin. Any injection into a person with a compromised immune system, especially one that is permanently in place, raises concerns about infection. Also, the pump is not completely practical in people who may be active. Now that people with HIV are living longer and becoming more active, the pump may not be something they want to deal with. And wearing a pump may be a constant reminder that they have HIV. However, a similar pump has been successfully used in diabetics for years, and few problems have been seen.

A second phase of study of the new drug is underway in San Francisco. Two sites, San Francisco General Hospital and Quest Clinical Research, will be conducting the trial locally while nine other U.S. sites will be enrolling patients. The study has fairly open inclusion criteria due to the need to study the drug in people who have taken all of the available treatments. Participants can be on any stable antiretroviral regimen during the 28-day study, or can choose to be on no concurrent therapy at all. A viral load of at least 5,000 is required. This study is a safety, proof of concept trial to learn about the effectiveness of the drug administered with the small pump. One arm of the study will use the subcutaneous delivery (by needle) at intervals and one arm will be used to compare to the 24-hour pump. Although drug continuation will not be offered after this 28-day study, participants will be eligible for a later trial yet to be designed.

Activists worked diligently with the company to ensure a trial design that would not only provide data for ongoing development of the drug, but also include people who needed it most. The company has been forthcoming with its plans for development of T-20 and has several phases of research planned. With each phase of development Trimeris has worked with the community and has changed study design to ensure the drug is tested in the most expeditious, productive, and ethical manner.

Encouraged so far

The present trial (003) is enrolling patients now, and will probably be fully enrolled by the end of October. Results should be presented at the retrovirus meeting in Chicago in January. We may know by early next year whether T-20 will be as promising as everyone thinks it is. There is concern with T-20 that the ever-present resistance problem encountered by all current HIV therapies will eventually show up. The resistance does appear, but seems to take longer to develop in the test tube than with most drugs. It is not known whether resistance will be the major problem it is in other HIV drugs like the protease inhibitors until further clinical studies are performed.

Jay Lalezari, principal investigator for T-20 at Quest Clinical Research, stated, "I think T-20 is the most promising new AIDS treatment directed at a new target of the HIV viral life cycle, but the biggest obstacle will be the mode of delivery with either the pump or by subcutaneous injections. I am encouraged by results I've seen so far in patients enrolled at Quest."

There are at least two other companies developing drugs to target the fusion process in the HIV life cycle. Both are in earlier development. It is encouraging given "AIDS exceptionalism," apathy, and market saturation of current anti-HIV drugs that there is energy toward development of brand new drugs targeted towards other parts of the HIV life cycle. Studies coming out in the next year will prove whether there is interest in continuing development. But first, proof that these new drugs are as promising as they appear to be will be the question people with AIDS, researchers, and pharmaceutical interests are waiting for.

It is critical that this research continue because so many people have taken the 14 other drugs that are available. These people desperately need treatment options that aren't cross resistant to all the therapies they have tried so that they can have yet another chance at survival.

For information about participating in the T-20 trial, call (415) 353-0800.
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Always watch for outdated information. This article first appeared in 1998. This material is designed to support, not replace, the relationship that exists between you and your doctor.

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