The Safety, Plasma Pharmacokinetics, and Antiviral Activity of Subcutaneous Enfuvirtide (T-20), a Peptide Inhibitor of gp41-Mediated Virus Fusion, in HIV-Infected Adults

Abstract

Enfuvirtide (T-20) is a novel antiretroviral agent that blocks HIV-1 cell fusion. A 28-day randomized dose-comparison study was conducted to determine the safety, pharmacokinetics, and antiviral activity of enfuvirtide in 78 HIV-infected adults, most with extensive treatment experience. Patients received enfuvirtide, added to a failing regimen, either by continuous subcutaneous infusion (CSI: 12.5, 25, 50 or 100 mg/day) or by subcutaneous (SC) injection (50 or 100 mg twice daily). Dose-related decreases in viral load were observed, with a maximum mean reduction from baseline of 1.6 log(10) copies/ml (p< 0.001) seen in the 100 mg bid SC group. Most responses diminished by 28 days. Plasma pharmacokinetics and antiviral responses were more consistent for SC injection than for CSI because of technical difficulties experienced with CSI. Injection site reactions were common but generally mild. These results indicate that enfuvirtide is a promising new therapeutic agent for HIV-infected patients, including those with prior antiretroviral treatment.

Novel Recombinant Engineered gp41 N-terminal Heptad Repeat Trimers and Their Potential as Anti-HIV-1 Therapeutics or Microbicides

“…N28Fd Was Much More Resistant Than T20 to Proteinase K Digestion-One of the principal disadvantages of the current gp41 CHR-based peptide drug T20 is its short half-life in vivo and high sensitivity to the proteolytic enzymes in blood (38). We speculated that the well folded secondary conformation of N28Fd trimer might gain resistance against proteolytic enzymes.…”

A small molecule HIV-1 inhibitor that targets the HIV-1 envelope and inhibits CD4 receptor binding

“…Structural information of the HIV-1 envelope has been provided by x-ray crystallography studies of the gp120 core protein complexed with a two-domain fragment of CD4 and a monoclonal antibody (13,14). Proof of concept for entry targets has been obtained in clinical trials using the attachment inhibitor PRO542 (a CD4-IgG fusion protein) (15,16), the CCR5 coreceptor antagonist SCH-C, ¶ and the fusion inhibitor enfuvirtide (17)(18)(19). In this study, a small molecule inhibitor of viral entry, BMS-378806, is characterized with regards to its antiviral activity, inhibition mechanism, resistance profile, and preliminary pharmacokinetic properties.…”

Toward a live microbial microbicide for HIV: Commensal bacteria secreting an HIV fusion inhibitor peptide

“…HIV C-peptides are potent entry inhibitors that are highly conserved between different isolates, do not require disulfide bonding or other posttranslational modifications, and are active against direct and trans infection of multiple primary cell types (12,13). One C-peptide, T-20 (enfuvirtide), is currently in clinical use as a salvage antiretroviral therapy (14).…”