A New Type of Anti-HIV Drugs: Fusion Inhibitors
The fusion inhibitor that is the furthest along in development is called T-20. It interferes with HIV entering a cell by binding to part of the HIV envelope.
It is well known by persons with HIV, their friends and families, and their healthcare providers that there are problems (as well as benefits) with the current anti-HIV treatments, also known as antiretrovirals. We don't have therapy for HIV that is curative, so people who need and choose treatment will be taking it for a long time. No one antiretroviral drug is powerful enough to suppress HIV by itself, so the current drugs have to be taken in combination with multiple others. Many people have trouble taking antiretrovirals, including problems with side effects or trouble taking pills on the right schedule, which may be very complex. For some people, antiretroviral therapy may not suppress their HIV or may only suppress it temporarily. Thus, we need drugs that are more powerful, have fewer side effects, and are easier to take.
There are many potential new anti-HIV drugs under investigation. Many of these drugs work the same way as the current therapies, but are hoped to be more potent, work against strains of HIV that are resistant to current agents, or have fewer side effects. There are some other investigational drugs that inhibit HIV by a different way. At least two such drugs have been shown to have anti-HIV effects in humans.
What is This New Target?
In order to understand this new target, you need to know that HIV attaches to the surface of certain cells, enters the cell, and goes through several steps to make more copies of itself. The new viruses are then released from the cell and go on to attach to and infect other cells. Currently available antiretrovirals inhibit HIV by interfering with steps inside the cell. The new target is on the outside (surface) of the cell. The process of the virus attaching to the cell surface is called fusion. Drugs that inhibit this process are called fusion inhibitors. This process has multiple steps, and different fusion inhibitors are designed to interfere with different parts of this process. When HIV attaches to the surface of a cell, a specific part of HIV (its envelope) attaches to a specific place on the cell surface (a protein or receptor). The main receptor that HIV attaches to is called CD4, but there are also other receptors (called co-receptors) that are essential to this process. Examples of other co-receptors are CCR5 and CXCR4.
What are These New Drugs Called and What Do We Know About Them?
The fusion inhibitor that is the furthest along in development is called T-20 (formerly pentafusion). It interferes with HIV entering a cell by binding to part of the HIV envelope called gp41. Studies in people have shown that T-20 can decrease HIV RNA (viral load) in blood, proving the concept that a fusion inhibitor can suppress HIV. Most of the experience with T-20 has been in patients who have taken other antiretrovirals. One study was done in persons with HIV who had used a median of 11 previous drugs. When they were given T-20 and other antiretrovirals (selected on the basis of the results of resistance testing), 55% to 60% had at least a 1 log decrease in HIV RNA and one third had HIV RNA decrease to less than 400 copies/mL after 16 weeks. (A 1 log decrease means a 10 times decrease in HIV RNA.) It is hard to know exactly what role T-20 played in the viral load decrease, but it shows that when T-20 is given in combination with other drugs, HIV can be suppressed even in patients who have had lots of previous treatment.
The main issue with T-20 (and with all of the fusion inhibitors currently) is that the drug isn't orally absorbed, and must be given by daily injection under the skin, like insulin. The main side effect seen with T-20 is mild to moderate reactions at the site of the T-20 injections. Another issue is that resistance to T-20 has been seen. T-20 is currently available only via research studies.
The makers of T-20 have designed another fusion inhibitor called T-1249, which also binds to gp41, and which they hope will be more difficult for HIV to develop resistance to. Studies in humans are starting, and it too must be administered by an injection under the skin.
This compound is a protein that has part of the CD4 protein and part of a human antibody (immunoglobulin G). In vitro (in the test tube) and in an animal model, PRO 542 has anti-HIV activity. Very early results from the first human study of PRO 542 have been reported. Single injections of PRO 542 have been given to three to six people at one of four doses. At the highest dose, decreases in HIV RNA were seen, with no significant side effects. Additional studies with more people treated for longer will be of interest.
In vitro (in the test tube), AMD-3100 has been shown to bind the co-receptor CXCR4 and inhibit HIV. AMD-3100 has been safe in animals and in a small study of normal volunteers. The first study of AMD-3100 in HIV-infected patients is going on now in three places, including the University of Washington AIDS Clinical Trials Unit. It will prove whether this compound has anti-HIV activity in people. Like the other fusion inhibitors, AMD-3100 is not absorbed orally. For this first study, the drug is being given by continuous infusion into a vein for 10 days.