Synthetic drug reduces HIV virus levels in blood
Intravenous form will limit use of T-20
A recently published report on the effects of the synthetic peptide inhibitor T-20 administered as monotherapy to 16 HIV-infected adults during a trial at the University of Alabama at Birmingham shows that the drug can, by itself, reduce virus levels by up to 99% when given at a concentration of 100 mg twice daily.
T-20 works by fusing with the HIV virus, thereby blocking cell entry, rather than by reducing virus levels already present in cells. The study found that over the two-week trial period, the efficacy of T-20 in blocking new virus infection was comparable to that of protease and reverse transcriptase inhibitors.1
The trial, led by J. Michael Kilby, MD, assistant professor of medicine at UAB and medical director of the UAB 1917 Clinic, has been met with reservations by some researchers. The number of subjects was small and the duration of the study brief, critics say. The molecular size of the drug means it must be given by injection, which makes it presently impractical if not impossible for most patients, more so given the compliance problems associated with oral administration in triple-drug therapy.
"There’s no peptide drug that’s been successful in other than intravenous form," says Jeffery Laurence, MD, director of the Laboratory for AIDS Research at New York Hospital, Cornell Medical College. "I think this is going to be a model of something interesting to look at. Maybe someone will come up with a drug you can take in pill form, but right now I think it’s a dramatic effect."
Laurence says use the new drug will be limited. "There are people who have continuous intravenous pumps, so it’s not totally impossible, but those are a very small percentage of the AIDS population," he says. "The likelihood that this is going to be a therapy that’s going to be usable for the 800,000 infected people in America is remote because it’s intravenous."
Promising concept needs further study
Also, HIV has thus far found ways to become resistant to peptides. In an editorial accompanying publication of the Alabama study in Nature Medicine, Douglas Richman, MD, cautioned that much further study is needed to determine long-term tolerance and toxicity. He also expresses concern about the drug’s hydrophobicity.2
Yet, as Kilby points out, "There are different reasons to be enthusiastic about research. Sometimes we are thrilled because a drug is matured and studied to the point that it’s ready to be released for general use. On the other end of the spectrum, sometimes our excitement is because there is just the proof of concept, the demonstration that an approach to therapy has any merit. That’s what this study is all about. So when we hear criticism that this is preliminary and needs further study, I’m the first to agree.
"To our knowledge, no one has ever inhibited the entry of virus into cells successfully in patients for any viral infection," Richman continues. "So the concept of being able to block a virus before it ever enters the cell is an intriguing one, and one that has a lot of potential."
The degree to which T-20 reduced the level of AIDS virus in the blood is impressive. Study subjects on the highest dosage experienced reductions of up to 99% within the two-week time frame, making it as potent as the currently prescribed forms of triple-drug therapy, with few side effects. If the efficacy and relative absence of side effects hold true over long exposure to this peptide, and a usable format for it can be developed, it could have a major edge over other chemotherapeutic agents.
Nava Sarver, PhD, chief of the targeted interventions branch of the Division of AIDS at the National Institute of Allergies and Infectious Diseases in Bethesda, MD, is optimistic about the possibilities for T-20. "What people seem to forget is that this is just the beginning of a new drug," Sarver says. "Right now, it has to be given by injection. Clearly, this is not going to be user-friendly and available to the large population if we leave it in that form. But nobody thinks that this is going to remain in that form.
"There are a lot of capable molecular biologists, structural biologists, who can determine the exact three-dimensional structure of this peptide and then develop non-peptidal mimetics, and these can probably be developed into an oral formulation," she says. "Clearly, it’s going to be used in combination with other drugs."
Blocking virus infection from the outset
T-20’s interaction with HIV before it enters cells opens a completely new avenue of attack, always a welcome event in disease management. "This is a new agent that blocks virus infection from the outset, and that is of course an advantage over all the other drugs we have because you are not fighting the virus that is replicating but trying to prevent the virus from establishing itself to begin with," Sarver says. "There has been a voluminous amount of information in vitro and in animal models about this drug."
Sarver also sees T-20 as immediately beneficial, even in its current injection-only form. T-20 would be highly useful in eradicating the reservoir of latent virus cells that remain even when viral load is undetectable, she says. Unless those cells are destroyed, HIV patients can become viremic again and the disease can rekindle itself. One approach being studied is activating those cells and causing them to start replicating the virus so they kill themselves under cover of very heavy antiretroviral therapy. Thus, the virus that is coming out does not infect other cells.
"If, for example, we do these studies, which are very highly experimental — there aren’t many people doing them because there is considerable risk and we don’t know how it’s going to end up — T-20 might be the perfect drug to give during this activation process to block the infection of other cells," says Sarver. "In this particular experiment where you try to activate the virus and to block other cells from becoming infected with the virus as it’s coming out of the latent cells, T-20 would be the perfect drug, even in its current form. This is really an area where my branch is looking for new opportunities for therapeutic intervention."
Use in postexposure prophylaxis
One use for T-20 that comes quickly to Kilby’s mind is treatment for someone immediately after they’ve been exposed to HIV. "A health care worker who’s had a needlestick, or even a pregnant woman who’s about to deliver a baby—I’m just speculating, these aren’t things we’re testing now—that would be an interesting place to use it, at the moment the virus is trying to establish a brand-new infection in someone. . . . You could think about the time in the future when you could give them perhaps a single injection, or a series of injections, that would prevent the virus from ever getting into the cells. Unfortunately, you can’t use this as a vaccine. . . . It looks like this drug has to be present at high levels at the same time the virus is present, but that doesn’t negate the possibility of a postexposure prophylaxis or immediate treatment when someone’s exposed.
"We’re currently involved in a phase two study at 12 centers around the country where patients are being enrolled regardless of their previous treatment, so it’s open to patients who have been on a variety of available therapies and have not responded adequately. The things that are different about this trial, other than there are more patients at more sites, is that they’re being randomized into groups that receive the drug subcutaneously. These patients will be able to administer shots to themselves, very much analogous to insulin therapy." Patients in the current trial will be able to take T-20 in combination with other therapies.
T-20 is analogous to insulin in that it’s a piece of protein that can’t be made in a pill form but potentially could be self-administered by patients at home. Some patients in the current trial will receive the medicine subcutaneously through a pump of exactly the same type as is used by some brittle diabetics to self-administer insulin at a steady rate.
References
1. Kilby JM, Hopkins S, Venetta T, et al. Potent suppression of HIV-1 replication in humans by T-20, a peptide inhibitor of Gp41-mediated virus entry. Nat Med 1998; 11:1,302-1,307.
2. Richman D. Nailing down another HIV target. Nat Med 1998; 11:1,232.
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