Enfuvirtide

Enfuvirtide must be administered parenterally it is associated with frequent and potentially serious side effects (see below). At the time of this writing, enfuvirtide is the only drug of its type, but other HIV entry inhibitors are currently in development, and the use of these drugs may be expanded in the future if newer, safer agents reach the market.86 

Mechanism of Action. As indicated, enfuvirtide inhibits the ability of HIV to bind to, and enter, susceptible host cells such as CD4 lymphocytes. The drug actually binds to specific components on the outer glycoprotein envelop of the virus, thereby retarding the ability of the virus to change its shape in preparation for adsorbing to the surface of the host cell. If the virus cannot attach to host cells, the risk of infection is reduced. 

Adverse Effects. Enfuvirtide must be administered by subcutaneous injection, and local pain and irritation occurs at the injection site in most patients. Other common side effects include peripheral neuropathy and immune complex reactions that can lead to serious problems including respiratory distress syndrome, kidney dysfunction, and possibly Guillain-Barre syndrome. 

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Env sequences both temporally and between patients. Two drugs that target HIV-1 entry, enfuvirtide and maraviroc, are now licensed for treatment of HIV-1 infection. The efficacy of these drugs validates entry as a point of intervention in viral hfe cycles and, in the context of HIV treatment, contributes to the growing armamentarium of antivirals which, in multidrug combinations, can effectively inhibit viral replication and prevent disease progression. 

This chapter is intended to provide an overview of HIV-1 entry inhibitors, focusing on the mechanism of action, development, and knowledge of viral resistance to the currently available entry inhibitors, enfuvirtide and maraviroc. Although reversed relative to their order in the entry process, enfuvirtide is discussed first due to the greater clinical experience with this drug. 

The first study to demonstrate the activity of enfuvirtide in HIV-infected patients (Kilby et al. 1998) showed that patients receiving the maximum 100 mg intravenous dose had maximum median declines in HIV-1 RNA of -1.96 logjo copies/mL through 14 days. Several additional studies (Kilby et al. 2002 Lalezari et al. 2003a, b) further demonstrated the safety and efficacy of enfuvirtide and led to the selection of twice-daily subcutaneous injections of a 90 mg nominal dose for testing in the TORO (T-20 vs. optimized regimen only) pivotal clinical trials. 

Data were pooled from the TORO-1 and -2 studies for 48 week efficacy analyses (Nelson et al. 2005). These generally confirmed the 24 week findings and also demonstrated the durability of virological response - in both the enfuvirtide -h OB and OB only groups only about 7% of patients met virological failure criteria between 24 and 48 weeks. 

Chemical Society s Southeastern Region for work demonstrating the commercial feasibihty of the manufacture of enfuvirtide. 

In contrast to the wide range of phenotypic susceptibility of viruses to enfuvirtide, analyses of gp41 sequences at entry into clinical studies show relatively little variation within the gp41 aa 36 5 region representing the binding site of enfuvirtide (described later). The most common polymorphism, N42S ( 16% prevalence... 

One second-generation peptide, T-1249, was developed as a follow-on to enfuvirtide and progressed into phase II clinical studies (Lalezari et al. 2004, 2005b). The sequence of T-1249 was derived from HIV-1, HIV-2, and SIV HR-2 domains. 

T-1249 demonstrated substantial activity against enfuvirtide-resistant viruses in clinical studies (Melby et al. 2007a) however, development was discontinued due to formulation issues. Additional peptides with more potent activity were subsequently designed, which also showed much improved pharmacokinetic properties (Dwyer et al. 2007) however, the availability of oral agents in other new classes makes the likelihood of the development of these agents uncertain. 

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