AIDS Community Research Initiative of America (ACRIA) - Fall 2003 / Winter 2004

Fuzeon (enfuvirtide, T-20) ushered in a new class of anti-HIV drugs (fusion inhibitors) when it received FDA approval in March 2003. For people whose HIV had become resistant to many drugs from the other classes, it offered new hope of bringing viral loads down below detection, but it came with two major obstacles. Since the stomach destroys the drug, it can't be taken as a pill, but has to be injected twice a day under the skin. And it has a retail price of over $25,000 a year - nearly three times that of any other anti-HIV drug.

Background: Fuzeon was originally developed by Trimeris (hence the "T" in T-20), a small company that conducted the first studies of the drug. In 1999, Trimeris partnered with the much larger (and better-financed) Hoffmann-La Roche to further develop and manufacture the drug.

As the first drug in a new class, Fuzeon entered the scene with the same kind of splash that accompanied Retrovir (AZT), the first antiretroviral, and Invirase (saquinavir), the first protease inhibitor. But as in those cases, the anticipation seems to have exceeded the actual event and, once again, the drug came with a price that set a new precedent.

Clinical trials have found that Fuzeon works for some people who have tried and failed other anti-HIV drugs, but usually only if it can be combined with older drugs that the virus is still sensitive to. In the TORO studies (T-20 vs. Optimized Regimen Only), nearly 1,000 people who had used an average of 12 antiretrovirals and were resistant to drugs from all three classes chose an "optimized" regimen of approved drugs. The regimens were individualized based on resistance testing and each person's treatment history. Two-thirds of the trial participants then added Fuzeon to their optimized regimen and the rest used only their optimized regimen. After 11 months, 18% of people taking Fuzeon had viral loads below 50 compared to 8% of those who weren't taking Fuzeon. People taking Fuzeon had an average increase of 91 in their CD4 counts compared to a rise of 45 for those on the optimized regimen alone. While adding Fuzeon worked more than twice as well as taking the optimized regimen alone, the fact remains that 82% of people on Fuzeon didn't achieve viral loads below 50 (the gold standard in treatment today, and the drop that is usually needed to keep viral loads low over time).

These modest results did not seem to dampen enthusiasm over Fuzeon's approval. And they did not prevent Roche from charging a price even higher than the most pessimistic forecasts. Roche says that the drug's manufacturing process requires the high price, and it is true that Fuzeon is the most difficult antiretroviral to make, with over 100 steps required for each batch. But many activists said that did not justify Fuzeon's price, and their protests helped AIDS Drug Assistance Programs (ADAPs) across the country negotiate significant price reductions.

According to the TORO studies, Fuzeon works best in people who have: taken less than ten antiretrovirals; a viral load below 100,000; a CD4 count above 100; and two other anti-HIV drugs that still work against their virus. 80% of people who had all these characteristics were able to get their viral loads below 50 with Fuzeon. But if you don't meet these criteria, your chances are worse. For example, people who had only one antiretroviral available saw viral load drops of just 0.2 logs (37%) after six months on Fuzeon, a result that is so minimal that it could be due to normal fluctuations. Those who had three or four drugs available saw viral load drops of 2.3 logs (99.5%) - an impressive change. So people whose virus is resistant to all of the approved drugs will most likely not benefit by adding Fuzeon to a failing regimen. Many people have waited to start Fuzeon until they could get access to newer drugs like tipranavir (an experimental protease inhibitor) through clinical trials, so that they could start both drugs together.

The biggest challenges Fuzeon users face are the twice-daily injections and problematic injection site reactions. Roche has published detailed information about how to prepare and inject Fuzeon, and anyone starting it needs to take great care to learn how to use the drug properly. The drug comes as a powder that must be mixed with sterile water - it can take up to 45 minutes to properly dissolve (usually about 15), and must not be shaken. Once mixed, it should be used right away (two doses can be made at once if the second is refrigerated). Similarly, the injections must be given correctly to minimize skin reactions and ensure that the drug is delivered properly. People starting Fuzeon must be carefully trained by their healthcare providers to make sure they know how to mix and inject the drug properly.

Fuzeon's difficult injections may have had an effect on its popularity. As of October 2003, Roche had received only 5,700 requests for Fuzeon - less than expected. Other people have had difficulty getting their insurance or ADAP to pay for the drug. People considering Fuzeon should be aware of the barriers to its use and prepare for them before starting.

Side Effects: Almost everyone who takes Fuzeon gets injection site reactions (ISRs), which can include itching, swelling, redness, pain or tenderness, hardened skin, and bumps. The reactions are usually mild to moderate, but can be severe in a few people. The best way to minimize them is to follow the preparation and injection instructions carefully. There are also detailed suggestions at the drug's website (www.fuzeon.com).

Fuzeon has caused a serious allergic reaction in less than 1% of people in clinical trials - anyone who has trouble breathing, fever with vomiting and a skin rash, blood in the urine, or swelling of the feet while taking the drug should call their healthcare provider immediately.

In clinical trials, people taking Fuzeon got bacterial pneumonia more often than people who weren't taking Fuzeon, especially those who had lower CD4 counts, higher viral loads, used injection drugs, smoked, or had lung disease in the past. It's not known how, or even whether, Fuzeon contributed to this, only that people taking Fuzeon in trials were more likely to get bacterial pneumonia.

Other side effects seen in people using Fuzeon include pain and numbness in the feet or legs, loss of sleep, depression, decreased appetite, weakness or loss of strength, muscle pain, constipation, and pancreas problems.

Drug Interactions: Fuzeon does not seem to interact with other antiretrovirals, and there are no other drug interactions listed in the package insert.

When To Consider It: Fuzeon is approved for use only in people whose HIV has become resistant to available antiretrovirals. Because of the drug's difficult dosing and high cost, it's best used only by people who need the drug to put together an effective treatment regimen. Since Fuzeon is the first drug in its class and works at a completely different point in HIV's lifecycle, no cross-resistance with drugs from the other classes has been seen. But trials have shown that Fuzeon doesn't work if a person has no other antiretrovirals available - at least one, or better yet, two other drugs are needed to keep viral loads below detection.

Early studies have shown that people whose virus has become resistant to Fuzeon can benefit by switching to T-1249, a fusion inhibitor that's in clinical trials. This is especially true for people with resistance who have taken Fuzeon for less than 11 months.

Fuzeon Tips:

• Fuzeon should be injected every 12 hours. Delaying a dose by more than an hour increases the risk of developing resistance to the drug.
• Some users have experienced syringe failures - Fuzeon leaking out from the "hub" (the point where the needle meets the syringe). If this happens, contact Roche at 877-438-9366 and report the problem. If you weren't able to take your full dose, they'll usually recommend that you mix another dose and will add extra drug to your next shipment to make up for the lost dose.
• A study looking at techniques that may minimize ISRs is starting. The methods being studied are gentle massage, heat from a warm moist cloth, hydrocortisone cream, self-injection, and having a partner inject the drug. We won't know which techniques work best until the study is finished, but people have reported some success with each of them.
• Other tricks people have tried to reduce ISRs include:
  • using an electric hand massager after the injection;
  • showering before injections to soften the skin;
  • avoiding shots in the butt if you have to sit for long periods;
  • wearing loose clothing to avoid irritating injection sites;
  • squeezing the skin like a bow tie and injecting into the sides, to lessen the pain and to make sure that you're not injecting into muscle.
• Find the injection sites that work best for you. For most people, the skin on the abdomen is best since it is often the loosest skin on the body. But one user finds injections in the upper thigh to work best - he feels that walking massages the site and leads to faster healing.
• The angle and depth of the needle may have an effect on the ISR - find the technique that works best for you.
• Roche recommends inserting the needle 3/4 of the way in, but users with little body fat have found that this may place the needle in the muscle rather than under the skin, leading to worse ISRs. Avoid injecting Fuzeon into muscle tissue - ask your healthcare provider for advice about changing your injection technique if needed.
• Fuzeon comes with safety syringes (the needle retracts after use), which have caused problems for some users. You can use other syringes if you need to, but ask your healthcare provider first.
• Some users have reported that mixing Fuzeon is easier and faster in a warmer room, so that the drug is at room temperature.
• As with all medications delivered by injection, Fuzeon may be a challenge for some people with a history of injection drug use. Some people balked at the thought of participating in the Fuzeon trials because they couldn't imagine using syringe needles regularly without triggering their disease of addiction. For other people who have used injection drugs, it may not be an issue.

Pregnancy: Fuzeon is classified as an FDA pregnancy category B drug. Studies in rats and rabbits have not found any harm to the fetus. Fuzeon has not been studied in pregnant women, so it should be used during pregnancy only if absolutely necessary.

Dose: 90 mg (1 mL) twice daily, as a subcutaneous (under the skin) injection in the upper arm, thigh, or abdomen. Each injection should be given at a different site than the one before and only where there is no injection site reaction from an earlier dose. Fuzeon should not be injected into moles, scar tissue, bruises, or the navel. The pediatric dose (ages 6 to 16 years old) is based on weight: 2 mg/kg twice a day up to a maximum of 90 mg twice a day. There's no recommendation for its use in children younger than 6 years old, since it hasn't been studied in them. The label includes a chart to find the correct dose based on weight.

FDA Approval: 2003

Manufacturer: Hoffmann-La Roche

Patient Assistance Program: 866-487-8591

Fuzeon Medical Questions: 877-4FUZEON (438-9366)

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