Fuzeon (Enfuvirtide, formerly T-20 and pentafuside)

IntroductionAccording to the National Institute of Allergy and Infectious Diseases, approximately 42 million people in the world are living with HIV/AIDS. In 2002, an estimated 5 million new HIV infections occurred worldwide (~14,000 infections per day).¹ Among the 14,000 new patients, an estimated 2000 were children under the age of 15 and 6000 were between 15 and 24 years of age. In the United States alone, the Centers for Disease Control and Prevention estimates that 850,000 to 950,000 people are living with HIV/AIDS and that 40,000 new infections are occurring each year.² Although the epidemiology is astounding, antiretroviral therapy has markedly improved within the last 15 years, leading to a decrease in AIDS-related deaths during the past 5 to 6 years. The introduction of highly active antiretroviral therapy has principally targeted the enzymes reverse transcrip-tase and protease for the treatment of HIV-1. Unfortunately, a number of clinically relevant drug-related adverse effects and an increase in drug resistance have been noted with such agents.² Fuzeon (enfuvirtide) injection, manufactured by Roche/Trimeris and recently approved by the FDA, represents a new class of agents known as fusion inhibitors. Pharmacology

Fuzeon, a synthetic 36 amino-acid peptide, binds to the glycoprotein 41 subunit (gp41) of HIV-1. The binding of Fuzeon to gp41 blocks the necessary conformational changes required for the fusion of the virus to the CD4+ cell membrane, and eventually the entry of the virus into the host cell.³

Clinical Trials

The T-20 plus Optimized Regimen Only 1 (TORO-1) study was an open-label, randomized trial investigating the use of Fuzeon when added to optimized background (OB) regimens. Subjects (n = 501) from the United States, Canada, Mexico, and Brazil were randomized 2:1 to receive Fuzeon 90 mg twice daily plus an OB regimen of 3 to 5 antiretroviral medications or OB alone. The primary end point was a change in HIV-1 RNA from baseline at week 24. The results showed a decrease in plasma HIV-1 RNA of 1.696 for the Fuzeon group and a log₁₀10 decrease of 0.764 log₁₀ for the control group (P < .001).⁴

Clotet and colleagues presented data from the TORO-2 study at the XIV International AIDS Conference. TORO-2 was an open-label, randomized, international study (in Europe and Australia) investigating the use of Fuzeon when added to OB regimens. Subjects (n = 504) were randomized 2:1 to receive Fuzeon 90 mg twice daily plus an OB regimen of 3 to 5 antiretro-viral medications or OB alone. The primary end point was a change in HIV-1 RNA from baseline at week 24. The results showed a decrease in plasma HIV-1 RNA of 1.43 log₁₀ for the Fuzeon group and a decrease of 0.65 log₁₀ for the control group (P < .0001).⁵SafetyThe most common adverse events reported in pooled safety analysis of both TORO-1 and TORO-2 were injection site reactions, diarrhea, nausea, fatigue, headache, insomnia, and vomiting. Additionally, an increased rate of bacterial pneumonia, with 1 death reported, was shown in clinical trials.

Outlook

Fuzeon is indicated for combination therapy with other antiretroviral agents for the treatment of HIV-1 infection in adults. The recommended adult dose of Fuzeon is 90 mg subcutaneously twice daily (at rotating sites). The recommended pediatric (age 6-16 years) dose is 2 mg/kg subcutaneously twice daily.

In addition to augmenting current therapy, Fuzeon may possibly assist in decreasing drug resistance and adverse effects associated with antiretroviral therapy. Despite positive clinical data, Fuzeon?s cost (~$20,000 per year), limited production, and parenteral administration are its setbacks. Further studies evaluating naive patients are warranted.

For a list of references, send a stamped, self-addressed envelope to: References Department, Attn. D. Ryan, Pharmacy Times, 241 Forsgate Drive, Jamesburg, NJ 08831; or send an e-mail request to: dryan@mwc.com.