Enfuvirtide

Enfuvirtide (INN) is an HIV fusion inhibitor, the first of a class of antiretroviral drugs used in combination therapy for the treatment of HIV-1 infection. It is marketed under the trade name Fuzeon (Roche).

Enfuvirtide
Clinical data
Trade namesFuzeon
AHFS/Drugs.comMonograph
License data
Pregnancy
category
  • AU: B2
  • US: B (No risk in non-human studies)
    Routes of
    administration    		Subcutaneous (SC)
    ATC code
    Legal status
    Legal status
    Pharmacokinetic data
    Bioavailability84.3% (SC)
    Protein binding92%
    MetabolismHepatic
    Elimination half-life3.8 hours
    Excretionunknown
    Identifiers
    CAS Number
    PubChem CID
    DrugBank
    ChemSpider
    UNII
    KEGG
    ChEBI
    ChEMBL
    NIAID ChemDB
    CompTox Dashboard (EPA)
    ECHA InfoCard100.169.201
    Chemical and physical data
    FormulaC204H301N51O64
    Molar mass4491.945 g·mol−1
    3D model (JSmol)
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    Enfuvirtide therapy costs an estimated US$25,000 per year in the United States. Its cost and inconvenient dosing regimen are factors behind its use as a reserve, for salvage therapy in patients with multi-drug resistant HIV.

    Structural formula

    Ac-Tyr-Thr-Ser-Leu-Ile-His-Ser-Leu-Ile-Glu-Glu-Ser-Gln-Asn-Gln-Gln-Glu-Lys-Asn-Glu-Gln-Glu-Leu-Leu-Glu-Leu-Asp-Lys-Trp-Ala-Ser-Leu-Trp-Asn-Trp-Phe-NH2

    History

    Enfuvirtide originated at Duke University, where researchers formed a pharmaceutical company known as Trimeris. Trimeris began development on enfuvirtide in 1996 and initially designated it T-20. In 1999, Trimeris entered into partnership with Hoffmann-La Roche to complete the development of the drug. It was approved by the U.S. Food and Drug Administration (FDA) on March 13, 2003[1] as the first HIV fusion inhibitor, a new class of antiretroviral drugs. It was approved on the basis of two studies which compared the effect of optimized regimens of antiretroviral medication with and without the addition of enfuvirtide on serum viral load.

    Pharmacology

    Mechanism of action

    Enfuvirtide works by disrupting the HIV-1 molecular machinery at the final stage of fusion with the target cell, preventing uninfected cells from becoming infected. A biomimetic peptide, enfuvirtide was designed to mimic components of the HIV-1 fusion machinery and displace them, preventing normal fusion. Drugs that disrupt fusion of virus and target cell are termed entry inhibitors or fusion inhibitors.

    HIV binds to the host CD4+ cell receptor via the viral protein gp120; gp41, a viral transmembrane protein, then undergoes a conformational change that assists in the fusion of the viral membrane to the host cell membrane. Enfuvirtide binds to gp41 preventing the creation of an entry pore for the capsid of the virus, keeping it out of the cell.[2]

    Enfuvirtide is also an activator of the chemotactic factor receptor, formyl peptide receptor 1, and thereby activates phagocytes and presumably other cells bearing this receptor (see formyl peptide receptors).[3] The physiological significance of this activation is unknown.

    Microbiology

    Enfuvirtide is considered to be active against HIV-1 only. Low activity against HIV-2 isolates has been demonstrated in vitro.[4]

    Variable susceptibility to enfuvirtide has been observed in clinical isolates, with acquired resistance the result of a mutated 10 amino acid motif in viral gp41. Primary resistance, however, has yet to be observed.[5]

    Clinical use

    Indications

    Enfuvirtide is indicated for the treatment of HIV-1 infection, in combination therapy with other antiretrovirals, in patients where all other treatments have failed.[6]

    Dosage forms

    By virtue of its peptide nature, enfuvirtide is marketed in injectable form. The lyophilised enfuvirtide powder must be reconstituted by the patient and administered twice daily by subcutaneous injection. Due to the chronic nature of this kind of therapy, this dosage form may be a major problem for the patient's adherence to this drug regimen.[7]

    Adverse effects

    Common adverse drug reactions (≥1% of patients) associated with enfuvirtide therapy include: injection site reactions (pain, hardening of skin, erythema, nodules, cysts, itch; experienced by nearly all patients, particularly in the first week), peripheral neuropathy, insomnia, depression, cough, dyspnoea, anorexia, arthralgia, infections (including bacterial pneumonia) and/or eosinophilia. Various hypersensitivity reactions occur infrequently (0.1–1% of patients), symptoms of which include rash, fever, nausea, vomiting, chills, rigors, hypotension, elevated hepatic transaminases; and possibly more severe reactions including respiratory distress, glomerulonephritis and/or anaphylaxis – rechallenge is not recommended.[6]

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    References
    1. "Drugs@FDA: FDA Approved Drug Products – Fuzeon (Click on 'Approval Date(s) and History, Letters, Labels, Reviews for NDA 021481')". accessdata.fda.gov. United States Food and Drug Administration. Retrieved 6 January 2019.
    2. Lalezari JP, Eron JJ, Carlson M, Cohen C, DeJesus E, Arduino RC, et al. (March 2003). "A phase II clinical study of the long-term safety and antiviral activity of enfuvirtide-based antiretroviral therapy". AIDS. 17 (5): 691–8. doi:10.1097/00002030-200303280-00007. PMID 12646792.
    3. Su SB, Gong WH, Gao JL, Shen WP, Grimm MC, Deng X, et al. (June 1999). "T20/DP178, an ectodomain peptide of human immunodeficiency virus type 1 gp41, is an activator of human phagocyte N-formyl peptide receptor". Blood. 93 (11): 3885–92. doi:10.1182/blood.V93.11.3885. PMID 10339497.
    4. Roche Products Pty Ltd. Fuzeon (Australian Approved Product Information). Dee Why (NSW): Roche; 2005.
    5. Greenberg ML, Cammack N (August 2004). "Resistance to enfuvirtide, the first HIV fusion inhibitor". The Journal of Antimicrobial Chemotherapy. 54 (2): 333–40. doi:10.1093/jac/dkh330. PMID 15231762.
    6. Rossi S, ed. (2006). Australian Medicines Handbook. Adelaide: Australian Medicines Handbook Pty Ltd. ISBN 0-9757919-2-3.
    7. Klein R (13 March 2003). "FDA approves Fuzeon". fda.gov. Archived from the original on 25 August 2009. Retrieved 2 July 2011.
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