U.S. Food and Drug Administration (FDA)-Approved Indications

Enfuvirtide is available as Fuzeon (Genentech USA, Inc.), an antiretroviral drug that is considered an HIV-1 gp4 fusion inhibitor. 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 gp41 subunit of the viral envelope glycoprotein and prevents the conformational changes required for the fusion of viral and cellular membranes (Genentech, 2019).

Labeled warnings and precautions include injection site reactions with pain, erythema, induration, nodules and cysts, which occurred in 98 % of patients receiving enfuvirtide, but led to discontinuation of the drug in only 3 %. Other events most frequently reported in subjects receiving enfuvirtide were diarrhea, nausea, and fatigue. Less common adverse events include headache, peripheral neuropathy, dizziness, insomnia, depression, decreased appetite, asthenia, myalgia, constipation and pancreatitis. The product labeling states that physicians should monitor patients for signs and symptoms of pneumonia. Although bacterial pneumonia was uncommon in clinical trials, more patients treated with enfuvirtide developed bacterial pneumonia than did patients who did not receive enfuvirtide. The most common adverse reactions are local injection site reactions, diarrhea, nausea, and fatigue.

Administration of Fuzeon with Biojector 2000 may result in neuralgia and/or paresthesia, bruising and hematomas. Patients receiving anticoagulants or persons with hemophilia, or other coagulation disorders, may have a higher risk of postinjection bleeding. Patients treated with combination antiretroviral therapy, including Fuzeon, may experience immune reconstitution syndrome requiring further evaluation and treatment.

Human Immunodeficiency Virus Type 1 (HIV-1) Infection

Fuzeon was approved by the Food and Drug Administration (FDA) for the combination treatment of human immunodeficiency virus (HIV) infection in adults and children (older than 6 years of age) who have ongoing viral replication despite ongoing anti-retroviral therapy. Enfuvirtide was the first in a class of HIV drugs known as fusion inhibitors.

Two 24-week randomized, controlled open-label studies (TORO-1 and TORO-2) of 955 HIV-infected treatment-experienced patients showed that patients 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 patients receiving therapy without enfuvirtide (Lalezari et al, 2003; Lazzarin et al, 2003).

The Panel on Treatment of HIV-Infected Pregnant Women and Prevention of Perinatal Transmission’s recommendations for use of anti-retroviral drugs in pregnant HIV-1-infected women (2012) stated that "Safety and PK [pharmacokinetic] data in pregnancy are insufficient to recommend use of the entry inhibitors enfuvirtide and maraviroc in ARV-naïve women during pregnancy. Use of these agents can be considered for women who have failed therapy with several other classes of ARV drugs after consultation with HIV and obstetric specialists". Furthermore, the Panel on Antiretroviral Therapy and Medical Management of HIV-Infected Children’s guidelines on "The use of anti-retroviral agents in pediatric HIV infection" (2012) stated that "Currently, data are insufficient to recommend use of enfuvirtide for initial therapy of children". Prospective pregnancy data from the Antiretroviral Pregnancy Registry (APR) are not sufficient to adequately assess the risk of birth defects or fetal outcomes (Genentech, 2019).

Coronavirus Disease 2019 (COVID-19)

Maleki and associates (2021) stated that there are currently no specific drugs and universal vaccines for coronavirus disease 2019 (COVID-19); thus, urgent effective measures are needed to discover and develop therapeutic agents. Applying peptide therapeutics and their related compounds is a promising strategy to achieve this objective. This review was written based on the literature search using several databases, previous studies, scientific reports, the current knowledge regarding the anti-microbial peptides (AMPs), and the authors’ personal analyses on the potential of the anti-viral peptides for the treatment of COVID-19. These investigators began with a brief description of SARS-CoV2 followed by a comprehensive description of anti-viral peptides (AVPs) including natural and synthetic AMPs or AVPs and peptidomimetics. Subsequently, the structural features, mechanisms of action, limitations, and therapeutic applications of these peptides were explained. The authors concluded that regarding the lack and the limitations of drugs against COVID-19, AMPs, AVPs, and other peptide-like compounds such as peptidomimetics have captured the attention of researchers due to their potential anti-viral activities. They noted that some of these compounds comprise unique properties and have demonstrated the potential to fight SARS-CoV2, especially melittin, lactoferrin, enfuvirtide (Enf), and rupintrivir that have the potential to enter animal and clinical trials for the treatment of COVID-19.

Ahmadi and colleagues (2021) noted that regarding the urgency of therapeutic measures for COVID-19 pandemic, the use of available drugs with FDA approval is preferred because of the less time and cost needed for their development. In silico drug re-purposing is an accurate way to speed up the screening of the existing FDA-approved drugs to find a therapeutic option for COVID-19. The similarity in SARS-CoV-2 and HIV-1 fusion mechanism to host cells can be a key point for inhibiting SARS-CoV-2 entry into host cells by HIV fusion inhibitors. Accordingly, in this study, an HIV-1 fusion inhibitor, Enf, was selected. The affinity and essential residues involving in the Enf binding to the S2 protein of SARS-CoV-2, HIV-1 gp41 protein and angiotensin-converting enzyme 2 (ACE-2) as a negative control, was examined using molecular docking. Enf-S2 and Enf-gp41 protein complexes were simulated by molecular dynamics (MD) in terms of binding affinity and stability. Based on the most important criteria such as docking score, cluster size, energy and dissociation constant, the strongest interaction was observed between Enf with the S2 protein. Furthermore, MD results confirmed that Enf-S2 protein interaction was remarkably stable and caused the S2 protein residues to undergo the fewest fluctuations. The authors concluded that the findings of this study showed that Enf had a good interaction with the most important residues of the HR2 domain of SARS-CoV-2 S2 protein and could act as a fusion inhibitor of this virus. Based on these findings as well as the present information regarding the pharmacological properties of Enf, these researchers stated that this FDA-approved anti-viral drug has the potential to enter the clinical trial phase for the treatment of the COVID-19.

Criteria for Initial Approval

Aetna considers enfuvirtide (Fuzeon) injection medically necessary for the treatment of human immunodeficiency virus type 1 (HIV-1) infection when either of the following criteria is met:

Aetna considers all other indications as experimental and investigational (for additional information, see Experimental and Investigational and Background sections).

Continuation of Therapy

Aetna considers continuation of enfuvirtide (Fuzeon) therapy medically necessary for treatment of HIV-1 infection when the member has had a positive or stable virologic response to enfuviritide.

Dosage and Administration

Fuzeon is available in a single-dose lyophilized powder for injection containing 108 mg enfuvirtide per vial and administered as a subcutenous injection. Fuzeon may be self-administered after training by medical professional using aseptic technique.

The recommended adult dose is 90 mg twice-daily; the dosage for pediatrics (6 years of age and older) weighing at least 11 kg is 2 mg per kg twice daily up to a maximum dose of 90 mg twice daily injected subcutaneously into the upper arm, anterior thigh or abdomen.

Source: Genentech, 2019

Experimental and Investigational

Aetna considers enfuvirtide experimental and investigational for the following indications (not an all-inclusive list) because its effectiveness for these indications has not been established.