PI Perspective #36

October 2003     View PDF     En español

Enfuvirtide (Fuzeon)

The FDA approved enfuvirtide (Fuzeon) in spring 2003 to use with other anti-HIV drugs in children age six and older and in adults who have used anti-HIV therapy before. Enfuvirtide is in a new class of drugs called entry inhibitors. The drug works at the start of HIV’s reproduction cycle by blocking its ability to infect an immune cell. This occurs at the point when HIV fuses to the cell’s outer wall in order to gain entry into it (see graphics). For more information, read New Hope for New Classes of Therapy in PI Perspective #35.

Who should use it?
Studies to date include people who have used and may have resistance to many drugs, and who have few options to put together a potent combination of drugs. For these people, enfuvirtide was able to reduce HIV levels and provide benefits. While enfuvirtide shows some activity in people resistant to many or all anti-HIV drugs, studies suggest it may be most effective in reducing HIV levels when used with at least one or two drugs that are still active against HIV. Because of its cost and the difficulties associated with using it, enfuvirtide is not recommended for first-time therapy or after only a few other drugs have been tried.

What does the research show?

How HIV fuses to a cell

 

Entry Inhibitor

Results from two major studies (TORO 1 and TORO 2) were pivotal in the FDA’s approval. Both included people with extensive use of anti-HIV therapy who were unable to control viral load. In each study, at study entry, CD4+ cell counts averaged below 100 and HIV levels averaged 100,000. TORO 1 included 491 people and TORO 2 had 504. In both, people used three to five anti-HIV drugs with or without enfuvirtide.

More people who used enfuvirtide reached undetectable viral loads and higher CD4+ cell counts. Of those on enfuvirtide, 37% (TORO 1) and 28% (TORO 2) achieved viral suppression below the limit of detection of the test compared to 16% (TORO 1) and 14% (TORO 2) of those not using it. Average CD4+ cell count increases among those on enfuvirtide were 76 (TORO 1) and 65 (TORO 2) compared to 32 (TORO 1) and 38 (TORO 2) in the group not taking the drug.

Another way to check the success of a regimen is its ability to decrease viral load by 1 log, regardless of whether or not a person reached “undetectable” levels. When combining results from both studies, slightly more than half of those on enfuvirtide had at least a 1 log reduction compared to about 25% of those not using the drug.

How to use it?
Enfuvirtide cannot be made into pill form for oral use and must be taken by injection. It is injected beneath the skin (not in a vein or muscle), twice a day about 12 hours apart. Each dose is 90mg, for a total daily dose of 180mg. For children weighing less than 94 pounds, doses are based on body weight (2.0mg/kg twice daily).

The drug is a powder and needs to be mixed with sterile saline solution. A prescription includes these, along with syringes and a sharps container for disposing of used syringes. Your doctor should give you information on how to mix the drug and provide guidance on self administration. Preparing the mixture and the injection site takes about 45 minutes, including the time it takes for the powder to dissolve. Unfortunately, the drug cannot be prepared ahead of time for several days use and should not be stored in the syringe to use later. Because injection site reactions may occur it’s important to change the injection site. Reusing syringes may lead to serious infections and should be avoided completely.

What about side effects?
The most common side effect, which occurred in almost everyone, is some degree of injection site reactions (redness, itching, swelling or skin irritation where the drug was injected into the skin). While this can be troublesome, only 5% of people stopped using the drug because of these side effects. In about 9% of people, however, reactions were severe enough to limit their activity and/or need an intervention to manage the reactions. Follow the training you receive from your doctor on how to use the drug; it is critical to minimizing these injection site problems. If you are not given guidance on how to do this, speak to your doctor and insist upon it. Other possible side effects, occurring in a small percentage of people taking the drug, include feeling tired (fatigue), sleep disturbance (insomnia) and pain or tingling in the legs, arms, hands and/or feet (peripheral neuropathy).

A small percent of people have a hypersensitivity (like an allergic) reaction to enfuvirtide, which could be life-threatening. Symptoms may include fever, chills, nausea, vomiting and shivering (rigors). People having these symptoms should contact their doctors immediately. Stopping the drug permanently may be necessary. For reasons that remain unclear, a slightly higher rate of bacterial pneumonia occurred among those using enfuvirtide.

What about drug resistance?
As with other anti-HIV drugs, HIV can develop resistance to enfuvirtide. Resistance occurs when the virus changes or mutates and the drug no longer controls the reproduction of HIV. However, studies suggest that enfuvirtide is effective against virus that has developed resistance to all other approved anti-HIV drugs.

Cross-resistance occurs when resistance to one drug makes other drugs less effective. If, or as other drugs like enfuvirtide become available, cross-resistance to similar drugs is possible. However, a similar drug that the company is working on (called T1249) has shown activity against virus that’s resistant to enfuvirtide. T1249 will also be an injection, but hopefully will require less frequent injections.

Are there concerns about drug interactions?
Studies have been done with other anti-HIV drugs and rifampin, a common tuberculosis medicine. Drug interactions were minor and did not require adjusting the dose of any drug. Whether or not enfuvirtide interacts with other drugs, like methadone, psychiatric medicines or street drugs, is not known. People are encouraged to discuss the possible drug interactions between all of the therapies and substances they are taking with their doctor and/or pharmacist.

Discussion
Perhaps the most important thing to think about when considering a new drug is how it fits into the arsenal of current therapies. Enfuvirtide will likely never be considered as part of a first line regimen—for someone who has never used anti-HIV drugs. This is because it’s difficult to prepare and inject, and injection site reactions can be problematic. This drug may not even be very appropriate as part of a second line regimen—for someone who has used one regimen and is looking for other options due to drug failure or side effects. Ultimately, the optimal role of this drug is as part of a third line or salvage therapy regimen.

Third line or salvage therapy often refers to a regimen for someone who has extensively used anti-HIV drugs and has developed resistance to many drugs in most classes. However, a true salvage therapy situation is when prominent resistance occurs to all drugs in all classes. It’s fairly rare for people to be in true salvage situations. Often, when looking at resistance test results and evaluating the history of anti-HIV drug use, many if not most people, while working with their doctors, can put together regimens that are active against HIV.

But how enfuvirtide fits into the picture of third line therapy is not wholly clear. If people can construct regimens—with the guidance of a doctor and resistance test results—that they believe will be potent without adding enfuvirtide, it may be a great option to hold enfuvirtide until later if or when options narrow even further. With that said, however, data show that enfuvirtide works best when paired with at least one other drug (preferably two) that’s active against HIV. Thus using enfuvirtide in a true salvage situation, when resistance to all drugs is likely, is not the best use of the drug.

For people facing third line therapy choices, enfuvirtide might not be the first option to turn to if other ones are available. A new protease inhibitor called tipranavir looms on the horizon. This drug will likely be available through expanded access programs in late 2003 or so. It appears to be active even in the face of resistance to all other protease inhibitors.

For some making third line therapy decisions, holding off on using enfuvirtide until tipranavir becomes available may still allow for using a viably potent regimen made up of drugs with only partial resistance. For others, in true salvage situations, holding off on using enfuvirtide until tipranavir is available may provide two new and potent drugs to pair up for hopefully better results. Finally, while enfuvirtide appears more potently able to impact HIV when paired with other anti-HIV drugs that are active against a person’s virus, it still provides some benefits in true salvage situations, even if it can’t be paired with another completely new drug. The results, however, may be short-lived in such situations. For more complete information on enfuvirtide, read the publication, Fuzeon.

Buying and Access
Enfuvirtide is available by prescription. Some states may cover enfuvirtide through their AIDS Drug Assistance Programs (ADAP). For information on your state ADAP eligibility and to find out if enfuvirtide is covered, contact Project Inform’s toll-free Hotline at 1-800-822-7422. Information is also available through the AIDS Treatment Data Network at 1-800-734-7104 or www.atdn.org. People who lack insurance, Medicaid, ADAP coverage or cannot afford to pay for the drug can sometimes gain free access to them through the manufacturer’s Patient Assistance Program.

Enfuvirtide: 866-694-6670

Currently, supplies of enfuvirtide are limited, so the company has set up the “Progressive Distribution Program”. Doctors apply on behalf of their patients. Once the supply meets the ongoing needs of the individual, the prescription is “activated” and the drug is shipped either to the patient or doctor. Prescriptions are filled on a first-come, first-serve basis. For more information, doctors should call 1-866-694-6670 to enroll their patients. Thereafter, patients may call directly to check on their status and ask questions. Enrollment forms are available at www.fuzeon.com.

Bottom Line on enfuvirtide

• Enfuvirtide is an injectable anti-HIV drug approved by the FDA for people with multi-drug resistance to other anti-HIV therapies.
• It appears safe, with the primary side effect of injection site reactions.
• Enfuvirtide appears to be active and useful for people who have failed other therapies and represents a hopeful new option for people.
• Being an injectable therapy, it may be difficult to use and requires training for doctors and patients alike to administer the drug to maximize benefits and minimize side effects.

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