|Drug class||HIV fusion inhibitor|
|Main uses||Treat and prevent HIV/AIDS|
|Side effects||Pain at site of injection, peripheral nerve damage, weight loss|
|Typical dose||90 mg BID|
|Elimination half-life||3.8 hours|
|Chemical and physical data|
|Molar mass||4491.945 g·mol−1|
|3D model (JSmol)|
Enfuvirtide, sold under the brand name Fuzeon, is a medication used to treat and prevent HIV/AIDS. It is used together with other medications when resistance has occurred. It is given by injection under the skin.
Common side effects include pain at the site of injection, peripheral nerve damage, and weight loss. Other side effects may include osteonecrosis, liver problems, allergic reactions, and immune reactivation syndrome. While there is no evidence of harm in pregnancy, such use has not been well studied. It is an HIV fusion inhibitor.
Enfuvirtide was approved for medical use in the United States and Europe in 2003. In the United Kingdom it costs the NHS about £1,100 a month as of 2021. This amount in the United States costs about 3,500 USD.
By virtue of its peptide nature, enfuvirtide is marketed in injectable form. The lyophilised enfuvirtide powder must be reconstituted 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 adherence to this drug.
Common side effects (≥1% of people) 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 liver transaminases; and possibly more severe reactions including respiratory distress, glomerulonephritis and/or anaphylaxis – rechallenge is not recommended.
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.
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). The physiological significance of this activation is unknown.
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.
Enfuvirtide is a 36-amino acid peptide with the following sequence:
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 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.
Society and culture
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.
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