HIV resistance to the fusion inhibitor enfuvirtide: mechanisms and clinical implications.

The increasing prevalence of HIV isolates resistant to one or multiple antiretroviral drugs has fueled the search for new agents that work by novel mechanisms. Enfuvirtide (ENF), licensed in 2002, is the first marketed antiretroviral (ARV) agent that targets viral entry. ENF blocks the virus replication cycle by binding to gp41, a critical component of the machinery used by HIV to enter host cells. As with all ARVs, HIV can evolve resistance to ENF. However, resistance to ENF appears to be somewhat more complex and can derive through either direct or indirect pathways. Direct resistance occurs when mutations in the first heptad repeat of gp41, which constitutes the ENF-binding site, reduce ENF binding. Indirect resistance is not attributable to changes in the ENF-binding site per se, but rather to changes in the HIV envelope glycoprotein (gp120) that reduce ENF susceptibility by more complex mechanisms. The extensive gp120 amino-acid sequence heterogeneity found in primary viral isolates results in unusually broad variability in susceptibility to ENF, and indeed to other classes of HIV entry inhibitors. Clinical data reported to date do not provide clear evidence that virological outcome of ENF therapy can be predicted by either genotypic or phenotypic analysis of viruses present in patients at initiation of ENF therapy. Although ENF offers an exciting opportunity to treat multi-drug resistant HIV, these observations suggest a greater understanding of ENF resistance may be required to ensure the most effective use of ENF in infected patients. Many aspects of the complexities observed in ENF resistance are likely to be relevant for other classes of HIV entry inhibitors currently in development.