Clinical UM Guideline


Subject:  Enfuvirtide (Fuzeon®)
Guideline #:  CG-DRUG-20Current Effective Date:  04/15/2014
Status:ReviewedLast Review Date:  02/13/2014

Description

Enfuvirtide (Fuzeon) (Hoffman-La Roche Inc., Nutley, NJ and Trimeris, Inc., Durham, NC) 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 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 and is used in conjunction with other anti-retroviral agents.

Clinical Indications

Medically Necessary:

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

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:

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

Enfuvirtide is considered not medically necessary for all other applications.

Coding

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.

HCPCS 
J1324Injection, enfuvirtide, 1 mg [Fuzeon]
  
ICD-9 Diagnosis[For dates of service prior to 10/01/2014]
 All diagnoses
  
ICD-10 Diagnosis[For dates of service on or after 10/01/2014]
 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. 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 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 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. 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% 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 two-year safety and tolerability study of enfuvirtide as salvage therapy was conducted in twenty-three Thai individuals with HIV-1 disease. Ninety-six weeks of treatment was completed by 74% (17) participants. Six participants withdrew prior to completion of the study, with two consents withdrawn, one adverse event reported, and three 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 (2012), 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 (2012) 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 (2013) 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.

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.

References

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.; for the 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. American Hospital Formulary Service® (AHFS). AHFS Drug Information 2013®. Bethesda, MD: American Society of Health-System Pharmacists®; 2013.
  2. Enfuvirtide (systemic). In: DrugPoints System [Internet database]. Greenwood Village, CO: Thomson Healthcare. Updated May 1, 2013. Available at: http://www.micromedexsolutions.com. Accessed on December 6, 2013.
  3. Fuzeon [Product Information], Hoffman-La Roche Inc., Nutley, NJ and Trimeris, Inc., Durham, NC; August 10, 2012. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/021481s025lbl.pdf. Accessed on December 6, 2013.
  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 February 12, 2013. Department of Health and Human Services. 1–239. Available at: http://aidsinfo.nih.gov/guidelines/html/1/adult-and-adolescent-treatment-guidelines/0/. Accessed on December 6, 2013.
  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 July 31, 2012. Department of Health and Human Services. Available at: http://aidsinfo.nih.gov/contentfiles/lvguidelines/perinatalgl.pdf. Accessed on December 20, 2013.
Websites for Additional Information
  1. Department of Health and Human Services. HIV/AIDS medical practice guidelines. Available at: http://aidsinfo.nih.gov/guidelines. Accessed on December 6, 2013.
Index

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.

History

Status

Date

Action

Reviewed02/13/2014Medical Policy & Technology Assessment Committee (MPTAC) review. Updated Description/Scope, Discussion, References section.  Added Websites section.
Reviewed02/14/2013MPTAC review. Updated Discussion, References sections.
Reviewed02/16/2012MPTAC review. Updated Discussion, References sections.
Reviewed02/17/2011MPTAC review. Updated Discussion, References sections.
Reviewed05/13/2010MPTAC review. Updated Coding, References sections.
Revised05/21/2009MPTAC review. Added medical necessity criteria for occupational postexposure prophylaxis. Added clarifying not medically necessary criteria. Rationale, references, websites and coding updated.
Reviewed05/15/2008MPTAC review.
New05/17/2007MPTAC review. Initial guideline development.