Entry Inhibitors

Enfuvirtide is a 36-amino-acid synthetic peptide whose sequence is derived from a part of the transmembrane pg41 region of HIV-1. Enfuvirtide is not active against HIV-2 but has a broad range of potencies against HIV-1 isolates.

MECHANISMS OF ACTION AND RESISTANCE The peptide blocks the interaction between the N36 and C34 sequences of the gp41 glycoprotein by binding to a hydrophobic groove in the N36 coil. This prevents formation of a six-helix bundle critical for membrane fusion and viral entry into the host cell. Enfuvirtide inhibits infection of CD4 cells by free virus particles, as well as cell-to-cell transmission of HIV-1 in vitro. Because of its unique mechanism of action, enfuvirtide retains activity against viruses that have become resistant to antiretroviral agents of other classes.

HIV-1 can develop resistance to enfuvirtide though specific mutations in the enfuvirtide-binding domain of gp41. Single amino acid substitutions can confer up to 450 times resistance in vitro, although high-level clinical resistance is generally associated with two or more amino acid changes.

Absorption, Distribution, and Elimination Enfuvirtide must be given parentally. Peak concentration after subcutaneous administration occurs on average 4 hours after dosing, with an apparent volume of distribution of 5.5 L. Pharmacokinetics of the subcutaneous drug are not affected by injection site. A deamidated metabolite at the C-terminal Phe is formed in humans, but no other significant metabolites are detected. The mean elimination t1/2 is 4 hours, necessitating twice-daily administration. The drug is highly bound by proteins, mainly albumin.

Adverse Effects The most prominent adverse effects of enfuvirtide are injection site reactions, including pain, erythema, induration, and nodules or cysts. These cause drug discontinuation in ~5% of patients. Use of enfuvirtide has been associated with increased lymphadenopathy and pneumonia. The causal role and underlying mechanism are under investigation.

Therapeutic Use Enfuvirtide is FDA-approved for use only in treatment-experienced adults who have evidence of HIV-1 replication despite ongoing antiretroviral therapy. Treatment response appears to be much more likely in patients with at least two other active drugs in the regimen, based on history and HIV genotype. Given its cost, inconvenience, and cutaneous toxicity, enfuvirtide is reserved for patients who have failed all other feasible antiretroviral regimens.

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