Enfuvirtide (Fuzeon) (Hoffman-La Roche Inc., Nutley, NJ and Trimeris, Inc., Durham, NC) was approved by the U.S. Food and Drug Administration (FDA) for use in conjunction with other anti-retroviral agents in the treatment of human immunodeficiency virus (HIV) infection in adults and children older than 6 years old who have ongoing viral replication despite ongoing antiretroviral therapy. Enfuvirtide is the first in a class of HIV drugs known as fusion inhibitors that interfere with the ability of the virus to enter the cell.

Medically Necessary:

Enfuvirtide is considered medically necessary when all of the following criteria are met:

• to treat HIV-infected individuals six years of age or older; and
• when used in combination with other anti-retroviral agents; and
• when the individual has failed* three or more prior months of therapy with a HAART (Highly Active Antiretroviral Therapy) regimen consisting of three or more antiretroviral agents.
  *Failure is defined as a confirmed HIV RNA level of greater than 50 copies/mL while on therapy.

Enfuvirtide is considered medically necessary for postexposure prophylaxis of HIV infection in healthcare workers and other individuals exposed occupationally via percutaneous injury or mucous membrane or nonintact skin contact with blood, tissues, or other body fluids associated with a risk for transmission of the HIV virus. (AHFS, 2010)

Not Medically Necessary:

Enfuvirtide is considered not medically necessary when the criteria above are not met.

Enfuvirtide is considered not medically necessary for all other applications.

The following codes for treatments and procedures applicable to this document are included below for informational purposes.  Inclusion or exclusion of a procedure, diagnosis or device code(s) does not constitute or imply member coverage or provider reimbursement policy.  Please refer to the member's contract benefits in effect at the time of service to determine coverage or non-coverage of these services as it applies to an individual member.

Future ICD-10 coding (effective 10/01/2013)
A draft of ICD-10 Coding related to this document, as it might look today, is available for reference and comments at: Appendix 1: Future ICD-10 coding

Enfuvirtide is an inhibitor of the fusion of HIV-1 with CD4⁺ cells. Enfuvirtide interferes with the entry of HIV-1 into cells by inhibiting fusion of viral and cellular membranes. Enfuvirtide binds to the first heptad-repeat (HR1) in the glycoprotein 41 (gp41) subunit of the viral envelope glycoprotein and prevents the conformational changes required for the fusion of viral and cellular membranes.

The U.S. Food and Drug Administration (FDA) approved enfuvirtide in 2003 in combination with other antiretroviral agents for the treatment of HIV-1 infection in treatment experienced individuals with HIV-1 replication despite ongoing antiretroviral therapy.

Two 24-week randomized, controlled open-label studies (TORO-1 and TORO-2) included 955 individuals with HIV-infected treatment-experience consisting of 3 to 5 antiretroviral agents selected on the basis of the subjects' prior treatment history and baseline genotypic and phenotypic viral resistance measurements. Subjects were randomized at a 2:1 ratio to subcutaneous enfuvirtide 90 mg given twice a day with background regimen or background regimen alone. Participants receiving enfuvirtide as a part of a combination of anti-HIV drugs experienced greater immunologic improvements and were twice as likely to achieve undetectable plasma levels of HIV compared to individuals receiving therapy without enfuvirtide (Lalezari, 2003; Lazarrin, 2003; Nelson 2005; Trottier, 2005). The two phase 3 multicenter trials required subjects to have either:

1. viremia despite 3 to 6 months prior therapy with a nucleoside reverse transcriptase inhibitor (NRTI), non-nucleoside reverse transcriptase inhibitor (NNRTI), and protease inhibitor (PI); or
2. viremia and documented resistance or intolerance to at least one drug in each of the NRTI, NNRTI, and PI classes.

In an optional 48-week extension study, Reynes (2007) and colleagues evaluated the long-term virologic and immunologic effects of enfuvirtide therapy. Out of the original combined cohort of 955 individuals, 362 (55%) completed 96 weeks of the study. At 96 weeks, mean copies of viral loads decreased from baseline -1.1 log₁₀ for participants that switched from the control group to enfuvirtide plus optimized background (OB) antiretroviral therapy versus -2.1 log₁₀ reduction in HIV-1-RNA copies for those in the treatment group. A viral load of less than 400 copies per millimeter was achieved for 26.5% of participants and 17.5% of the participants achieved less than 50 copies per millimeter. The investigators concluded the safety and efficacy of enfuvirtide plus OB were durable in the 96-week study.

According to the product information label (2009), there are no studies of enfuvirtide in antiretroviral naïve subjects. Additionally, there was insufficient data to establish recommended dosing for the pediatric population below 6 years of age (Product Information Label, 2009).

The United States Public Health Service guideline for the management of occupational exposure and postexposure prophylaxis (PEP) states that enfuvirtide has theoretic benefits for use in PEP, since its activity occurs before the virus enters the cell (Panlilio 2005). However, it is not routinely recommended for this use in part due to the inconvenience of the subcutaneous administration and the availability of other regimens.

The American Hospital Formulary Service (2010) states

Enfuvirtide is recommended as an alternative agent for use in conjunction with other antiretroviral agents for postexposure prophylaxis of HIV infection in health-care workers and other individuals exposed occupationally via percutaneous injury or mucous membrane or nonintact skin contact with blood, tissues, or other body fluids associated with a risk for transmission of the virus. Although enfuvirtide is not recommended for routine postexposure prophylaxis following occupational exposure to HIV because the drug is administered subcutaneously, some experts suggest that enfuvirtide can be considered for use in expanded regimens with expert consultation.

Frequent adverse events to the subcutaneous injections include local injection site reactions, diarrhea, nausea and fatigue. The product information label (2009) also warns of the need to monitor for signs and symptoms of systemic hypersensitivity reactions and for pneumonia and other opportunistic infections. In a randomized study by Lalezari (2008), the local injection site reactions were significantly reduced with the use of needle-free injection devices.

Peer Reviewed Publications:

1. Clotet B, Capetti A, Soto-Ramirez LE, et al. A randomized, controlled study evaluating an induction treatment strategy I which enfuvirtide was added to an oral, highly active antiretroviral therapy regimen in treatment-experienced patients: the INTENSE study. J Antimicrob Chemother. 2008; 62(6):1374-1378.
2. Lalezari JP, Henry K, O' Hearn M, et al.; TORO 1 Study Group. Enfuvirtide, an HIV-1 fusion inhibitor, for drug-resistant HIV infection in North and South America. N Engl J Med. 2003; 34(22):2175-2185.
3. Lalezari JP, Saag M, Walworth C, Larson P. An open-label safety study of enfuvirtide injection with a needle-free injection device or needle/syringe: the Biojector 2000 Open-label Safety Study (BOSS). AIDS Res Hum Retroviruses. 2008; 24(6):805-813.
4. Lazzarin A, Clotet B, Cooper D, et al.; TORO 2 Study Group. Efficacy of enfuvirtide in patients infected with drug-resistant HIV-1 in Europe and Australia. N Engl J Med. 2003; 34(22):2186-2195.
5. Nelson M, Arasteh K, Clotet B, et al. Durable efficacy of enfuvirtide over 48 weeks in heavily treatment-experienced HIV-1-infected individuals in the T-20 versus optimized background regimen only 1 and 2 clinical trials. J Acquir Immune Defic Syndr. 2005; 40(4):404-412.
6. Reynes J, Arasteh K, Clotet B, et al. TORO: ninety-six-week virologic and immunologic response and safety evaluation of enfuvirtide with an optimized background of antiretrovirals. AIDS Pat Care and STDs. 2007; 21(8):533-543.
7. Trottier B, Walmsley S, Reynes J, et al. Safety of enfuvirtide in combination with an optimized background of antiretrovirals in treatment-experienced HIV-1-infected adults over 48 weeks. J Acquir Immune Defic Syndr. 2005; 40(4):413-421.

Government Agency, Medical Society, and Other Authoritative Publications:

1. American Hospital Formulary Service (AHFS). AHFS Drug Information 2010. Bethesda, MD: American Society of Health-System Pharmacists, 2010.
2. Enfuvirtide (systemic). In: DrugPoints System [Internet database]. Greenwood Village, CO: Thomson Healthcare. Updated periodically. Available at: http://www.thomsonhc.com. Accessed on December 10, 2010.
3. Fuzeon [Product Information], Hoffman-La Roche Inc., Nutley, NJ and Trimeris, Inc., Durham, NC; December 22, 2009. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/021481s017lbl.pdf. Accessed on December 10, 2010.
4. Panlilio AL, Cardo DM, Grohskopf LA, et al. Updated U.S. Public Health Service guidelines for the management of occupational exposures to HIV and recommendations for postexposure prophylaxis. MMWR Recomm Rep. 2005; 54(RR-9):1-17. 

Enfuvirtide
Fuzeon

The use of specific product names is illustrative only. It is not intended to be a recommendation of one product over another, and is not intended to represent a complete listing of all products available.