Entry inhibitors are a new class of anti-HIV drugs that work by blocking the virus' ability to infect a cell. There are two general types of entry inhibitors: fusion inhibitors and attachment inhibitors. They may be joined by a third type in future years.
Enfuvirtide (T-20, Fuzeon), a fusion inhibitor approved by the Food and Drug Administration in 2003, is the first of this new class available for wide scale use. While enfuvirtide has proven to be potent, its side effects, mostly associated with the fact that it has to be injected with a syringe, have discouraged many people from using it. Still, others have been denied access because of the extremely high cost of the drug, which prevents many states from including it in their AIDS Drug Assistance Programs (ADAP). For more information on enfuvirtide, call Project Inform's toll-free hotline at 1-800-822-7422.
Many believe the greater promise for entry inhibitors will be realized with small molecule drugs. When large molecule drugs, like enfuvirtide, are taken orally, the digestive process breaks them into smaller pieces, thus rendering them ineffective. Therefore, they must be taken by injection. Small molecules drugs, however, are unaltered by the digestive system and can be taken by mouth, avoiding the problems associated with injections. Several are in development, including six that are in human studies, which we report on here.
HIV viral entry involves four steps. First, the virus attaches to the CD4+ protein, a receptor that appears on certain cells of the immune system. Then, it binds to a second surface protein on these cells, called a co-receptor. The most common co-receptors for HIV are CCR5 and CXCR4. Once it's anchored to the two receptors, the virus fuses its outer coat to the coat of the cell. Lastly, HIV sheds its own coat and injects its genetic material from its core into the cell.
There are compounds in development that target each of these entry steps. Most are still in test tube studies. The six entry inhibitors currently in human studies can be divided into two categories -- those that block the first step (virus attachment to the CD4+ protein) and those that block the second step (binding to a co-receptor).
BMS-488043 is an oral attachment inhibitor drug that binds to CD4+ receptors. By binding, it blocks the virus from attaching to the cell. It is currently being studied at two doses, 800mg and 1,800mg, twice a day. Preliminary data show that among the 12 people who were given the lower dose (800mg twice daily), viral load decreased an average of .73 logs compared to .02 log decrease among the three people who received a placebo. Information was not presented on the higher dose group, but will be forthcoming. Further studies are being planned.
TNX-355 is a monoclonal antibody of CD4+. It's a man-made antibody, binding to CD4+ cells in hopes of blocking the first step in the viral entry process -- attachment to the CD4+ receptor. In a small study, 22 people were given TNX-355 by injection either weekly or every two weeks in addition to their standard anti-HIV regimen for nine weeks. Viral load reductions of approximately 1 log were observed within 2 weeks of initiating TNX-355. However, viral load returned to pre-study levels by the end of nine weeks, with evidence of resistance. CD4+ cell counts fluctuated during the study, and maximum increases ranged between 103 and 257, with greatest increases being seen among those receiving weekly injections. One inherent limitation of many monoclonal antibodies is that the human body sometimes makes antibodies against the antibody, diminishing their effectiveness. An additional concern is that monoclonal antibodies are very expensive to make in the large quantities needed for chronic treatment.
PRO 542 from Progenics, mimics CD4+ cell receptors, causing HIV to bind to PRO 542 instead of CD4+ cells. In one study of heavily pre-treated people whose drug regimens were failing, viral load reductions of 60-80% were seen after a single dose of PRO 542. The results are promising and follow-up studies are planned. However, the drug must be given by subcutaneous injection, a clear liability.
Schering D is a small molecule oral drug that binds to the CCR5 receptor and thus prevents HIV from binding to this co-receptor. Recent data from a small dose finding study were encouraging. A total of 36 people, who were not on other anti-HIV drugs, received one of 4 doses (10mg, 25mg and 50mg) of Schering D every 12 hours for two weeks. An additional 12 people received a placebo. Viral load decreases were reported in all groups receiving Schering D, with the largest decrease seen at the highest doses (-1.08 logs, -1.56 logs and -1.62 logs respectively). No significant changes in viral load were seen in the placebo group.
UK-427,857 is another oral CCR5 blocker. Data presented last year from a small dose finding study, show it to be potent and well tolerated. A total of 16 people were given UK-427,857 at two dose levels and were compared to eight people given a placebo. At the higher dose, 100mg two times a day, seven out of eight people had a 1 log reduction in HIV viral load. Half the people taking the lower dose of 25mg two times a day had viral load decreases of greater than 0.5 logs. No serious side effects were reported in the study. As is the case with the Schering D drug, it is not clear whether the optimal dose has yet been determined for this drug.
GW-873140 is also an oral CCR5 blocker. In a small safety and dose finding study, the drug was found to be safe, with no serious side effects reported. The most common side effects were nausea, diarrhea and abdominal cramping. No data on anti-HIV effects were reported. Follow-up studies are planned.
The promise of entry inhibitors, especially small molecules, has many companies working on their own novel drugs. Many are still in pre-clinical development, and are years away from being available. However there are a number of promising candidates already in human studies. If these continue to show promise, some might reach wider human use within two or two and a half years.
People living with HIV need drugs that address new targets, which are easier to take and have fewer side effects. Entry inhibitors hold promise in these ways, but as always, the proof will come from clinical studies.
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