Clinical UM Guideline


Subject: Enfuvirtide (Fuzeon®)
Guideline #:  CG-DRUG-20 Publish Date:    12/12/2018
Status: Reviewed Last Review Date:    11/08/2018


This document addresses enfuvirtide (Fuzeon®) (Genentech, San Francisco, CA) which was approved by the U.S. Food and Drug Administration (FDA) as the first injectable agent in the treatment of human immunodeficiency virus (HIV) infection in adults and children older than 6 years of age 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 and is used in conjunction with other anti-retroviral agents.

Clinical Indications

Medically Necessary:

  1. Enfuvirtide is considered medically necessary when all of the following criteria are met:
    1. To treat HIV-infected individuals 6 years of age or older; and
    2. When used in combination with other anti-retroviral agents; and
    3. When the individual has failed* 3 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 ribonucleic acid (RNA) level of greater than 50 copies/mL while on therapy or intolerance due to drug toxicity.
  2. 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.

Not Medically Necessary:

  1. Enfuvirtide is considered not medically necessary when the criteria above are not met.
  2. 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.




Injection, enfuvirtide, 1 mg [Fuzeon]



ICD-10 Diagnosis



All diagnoses

Discussion/General Information

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. The 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 participants’ 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 III 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. Viral load reduction of greater than or equal to 1.0 log10 from baseline was considered a response. Out of the original combined cohort of 955 individuals, 362 (55%) individuals in the enfuvirtide treatment group completed 96 weeks of the study. At 96 weeks, mean copies of viral load 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 safety and efficacy of enfuvirtide plus OB were durable in the 96-week study.

In a subset analysis of the TORO study, body composition and metabolic parameters were evaluated at 48 weeks in participants from the enfuvirtide treatment group compared to the OB group (Cooper, 2011). There were no significant differences between the groups for increases in total cholesterol, high-density lipoprotein (HDL) and glucose. There was a significant mean change of body weight from baseline +0.99 kg (95% confidence interval [CI] +0.54- + 1.44) for the treatment group but there was no significant change from baseline for the OB control group. There was a significant difference in the mean change from baseline waist circumference between treatment groups of 1.73 (95% CI 0.27- 3.20). The mean changes in other anthropometric measurements between cohorts were not significantly different. The authors concluded regimens with enfuvirtide did not have an adverse effect on body composition and metabolic parameters when compared to OB antiretroviral regimens.

A 2-year safety and tolerability study of enfuvirtide as salvage therapy was conducted in 23 Thai individuals with HIV-1 disease. A total of 96 weeks of treatment was completed by 74% (17) participants. Of the 17 participants, 6 withdrew prior to completion of the study, with 2 consents withdrawn, 1 adverse event reported, and 3 deaths from HIV related complications. Local injection site reactions were the most common adverse event and good control of the HIV disease was reported.

According to the product information label (2016), 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.

Adverse Events and Warnings

Warnings and precautions from the FDA Product Information Label (2016) include the following:

The most common adverse reactions are local injection site reactions, diarrhea, nausea, and fatigue. In a randomized study by Lalezari (2008), the local injection site reactions were significantly reduced with the use of needle-free injection devices.

The updated U.S. Public Health Service guideline for the management of occupational exposure and postexposure prophylaxis (PEP) (Kuhar, 2013) states enfuvirtide:

…is not generally recommended as PEP, unless its use is deemed necessary during expert consultation due to its subcutaneous route of administration, significant side effects, and potential for development of anti-T20 antibodies that may cause false-positive HIV antibody tests among uninfected patients. 

Enfuvirtide is listed in the guideline as an alternative agent for use as PEP only with expert consultation.

The American Hospital Formulary Service (2018) states:

Enfuvirtide is used in conjunction with other antiretrovirals for postexposure prophylaxis of HIV infection following occupational exposure (PEP) in health-care personnel and other individuals exposed via percutaneous injury (e.g., needlestick, cut with sharp object) or mucous membrane or nonintact skin (e.g., chapped, abraded, dermatitis) contact with blood, tissue, or other body fluids that might contain HIV.

There are ongoing clinical trials studying enfuvirtide as a component of multidrug regimens for initial treatment of HIV infection, but the results of the pivotal trial need to be validated. Additional clinical trials are investigating the various combinations of anti-HIV drugs to determine the optimal combination and timing.


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. Cooper DA, Cordery DV, Reiss P, et al.; TORO 1 and TORO 2 Study Groups. The effects of enfuvirtide therapy on body composition and metabolic parameters over 48 weeks in the TORO body imaging substudy. HIV Med. 2011; 12:31-39.
  3. Joly V, Fagard C, Grondin C, et al.; S 130 Apollo Trial Group. Intensification of antiretroviral therapy through addition of enfuvirtide in naive HIV-1-infected patients with severe immunosuppression does not improve immunological response: results of a randomized multicenter trial (ANRS 130 Apollo). Antimicrob Agents Chemother. 2013; 57(2):758-765.
  4. 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.
  5. 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.
  6. 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.
  7. Morand-Joubert L, Ghosn J, Delaugerre C, et al.; Innove Study Group. Lack of benefit of 3-month intensification with enfuvirtide plus optimized background regimen (OBR) versus OBR alone in patients with multiple therapeutic failures: the INNOVE study. J Med Virol. 2012; 84(11):1710-1718.
  8. 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.
  9. Pichenot M, Deuffic-Burban S, Cuzin L, Yazdanpanah Y. Efficacy of new antiretroviral drugs in treatment-experienced HIV-infected patients: a systematic review and meta-analysis of recent randomized controlled trials. HIV Med. 2012; 13(3):148-155.
  10. Prasithsirikul W, Hanvanich M, Suwanagool S, et al. Two-year safety and tolerability study of enfuvirtide use in salvage therapy of Thai HIV-1 experienced cases. J Med Assoc Thai. 2011; 94(3):303-308.
  11. 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.
  12. 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. Enfuvirtide (systemic). In: DrugPoints® System [Internet database]. Truven Health Analytics, Greenwood Village, CO: Updated November 17, 2017. Available at: Accessed on October 16, 2018.
  2. Enfuvirtide Monograph. Lexicomp® Online, American Hospital Formulary Service® (AHFS®) Online, Hudson, Ohio, Lexi-Comp., Inc. Last revised August 13, 2018. Accessed on October 16, 2018.
  3. Fuzeon [Product Information], Genentech, San Francisco, CA. Revised December 2016. Available at:  Accessed on October 16, 2018.
  4. Kuhar DT, Henderson DK, Struble KA, et al.; US Public Health Service Working Group. Updated US Public Health Service guidelines for the management of occupational exposures to human immunodeficiency virus and recommendations for postexposure prophylaxis. Infect Control Hosp Epidemiol. 2013; 34(9):875-892.
  5. Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Reviewed May 30, 2018. Department of Health and Human Services. 1-239. Available at: Accessed on October 16, 2018.
  6. Panel on Treatment of HIV-Infected Pregnant Women and Prevention of Perinatal Transmission. Recommendations for use of antiretroviral drugs in pregnant HIV-1 women for maternal health and interventions to reduce perinatal HIV transmission in the United States. Reviewed October 26, 2016. Department of Health and Human Services. Available at: Accessed on October 16, 2018.
Websites for Additional Information
  1.  Department of Health and Human Services. HIV/AIDS medical practice guidelines. Available at: Accessed on October 16, 2018.


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.







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MPTAC review. Added medical necessity criteria for occupational post exposure prophylaxis. Added clarifying not medically necessary criteria. Rationale, references, websites and coding updated.



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