Enfuvirtide and Cutaneous Injection-Site Reactions
October 2012 | Volume 11 | Issue 10 | Original Article | 35 | Copyright © October 2012
Enfuvirtide belongs to a newer class of antiretroviral (ARV) agents called fusion inhibitors for the treatment of human immunodeficiency virus type 1 (HIV-1) infection. Enfuvirtide blocks attachment, binding, and entry of the viral capsid into the host CD4+ cell. Administration is only available subcutaneously in a twice-daily regimen particularly for those patients who have previously failed more than one ARV regimen. Common side effects of enfuvirtide administration include fatigue, insomnia, nausea, and diarrhea; however, injection-site reactions are the most common side effect and present in nearly all individuals undergoing treatment. The spectrum of cutaneous manifestations ranges from little to no reaction to cysts, nodules, induration, or sclerodermalike lesions. These reactions are mostly variants of iatrogenically induced hypersensitivity and are self-limited. J Drugs Dermatol.
Enfuvirtide, the prototype for a novel class of antiretroviral (ARV) agents deemed to be fusion protein inhibitors, is a prescription drug used for the treatment of human immunodeficiency virus (HIV-1) infection. It is a 36-amino-acid synthetic polypeptide and is the first agent of its class to be developed.1,3 Originating from the Trimeris, Inc research labs at Duke University (Durham, NC), enfuvirtide underwent development in 1996 with the designation T-20 and later underwent human clinical investigation under a partnership with Hoffmann-La Roche.2 The Food and Drug Administration (FDA) approved enfuvirtide for clinical use on March 13, 2003, at the conclusion of two T-20 vs Optimized Regimen Only studies (TORO). TORO 1 was conducted in North and South America, and TORO 2 was conducted in Europe and Australia. The TORO trials served to illustrate the additive benefit of adjunctive enfuvirtide in the setting of an optimized ARV regimen guided by phenotypic and genotypic resistance testing.3 Today, enfuvirtide is comarketed and sold under the trade name Fuzeon® by Genentech USA, Inc and Trimeris, Inc (San Francisco, CA).
HIV infectivity is dependent on incorporation and utilization of the host's intracellular machinery, thus requiring penetration beyond the host cell's membrane to replicate and persist. HIV achieves this through interaction of its surface envelope glycoprotein 120 (gp120) with the host's CD4 cellular membrane domains responsible for binding and attachment. Association of gp120 and the CD4 cell membrane receptors induces a conformational change in gp120, which hastens further interaction between gp120 and chemokine coreceptors (CXCR4 or CCR5) that are expressed on lymphocytes and mononuclear cells. The culmination of these interactions allows the transmembrane glycoprotein 41 (gp41) to undergo a conformational change that drives the host's cellular and viral membranes to fuse, creating an intercellular pore of substantial dimension that allows the viral capsid to pass into the CD4 cell intracellular matrix.
Enfuvirtide is derived from the heptad repeat 2 domain of gp41 of HIV type 1 (HIV-1).4 Unlikpe previous classes of ARV agents, enfuvirtide acts extracellularly to inhibit de novo infection by mimicking a critical amino-acid sequence and binding a region on gp41, which blocks conformational folding and impedes virus-cell membrane fusion and subsequent virus entry into target host cells.5
The dosing regimen for adults aged ≥16 years is 90 mg administered subcutaneously in the upper arm, abdomen, or anterior thigh twice daily, and the dosing regimen for children aged 6 to 16 years is 2 mg/kg twice daily up to a maximum of 90 mg twice daily.6,7 In the pediatric population, weight should be periodically monitored and the enfuvirtide dose adjusted accordingly (Table 1).6
Pharmacokinetics of enfuvirtide have shown that absorption profiles from the abdomen, anterior thigh, and arm are comparable; thus patients may gain more flexibility and reduced discomfort by rotating injection sites.4,8 Enfuvirtide accumulates in the subcutaneous region, diffuses throughout the immediate tissue, and gets absorbed into the blood.1 The concentration of enfuvirtide in the plasma (Cp) reaches a maximum concentration (Cmax) and declines in a single phase.9 Following a single subcutaneous dose of 90 mg, the mean Cmax (± standard deviation) was 4.59 ± 1.5 µg/mL.6 Following a 90-mg, twice-daily