By Liz Highleyman

Among the challenges of antiretroviral therapy is the emergence of drug resistance. In some cases, development of resistance to one agent can lead to cross-resistance to other drugs in the same class. Use of the HIV fusion inhibitor enfuvirtide (T-20; Fuzeon) can select for drug-resistant HIV-1 strains bearing mutations in the HR1 region of the viral envelope protein.

As described in the January 24, 2007 online edition of the Journal of Virology, researchers analyzed the properties of multiple envelope proteins isolated from 5 patients who experienced an initial viral load decline after starting enfuvirtide, followed by subsequent virological rebound due to emergence of enfuvirtide -resistant HIV.

Results

• Prior to enfuvirtide therapy, each patient harbored genetically and phenotypically diverse envelope proteins that used CCR5 and/or CXCR4 co-receptors to achieve membrane fusion.

• Co-receptor usage patterns of the envelope proteins isolated from 2 of the patients underwent homogenization following enfuvirtide therapy.

• In the other 3 subjects, recombination appeared to allow the introduction of a single HR1 sequence with enfuvirtide-resistance mutations into phenotypically distinct envelope proteins.

• Analysis of individual clones also revealed that prior to starting enfuvirtide, there was sometimes marked heterogeneity in the susceptibility of individual envelope proteins to co-receptor inhibitors.

• After virological failure, all envelope proteins acquired resistance to enfuvirtide, but exhibited no consistent change in their sensitivity to the fusion inhibitor T-1249 or to co-receptor inhibitors.

Conclusion

In summary, the authors concluded, "using patient-derived envelope proteins, we found that enfuvirtide failure was associated with emergence of high-level resistance to enfuvirtide due largely to mutations in HR1, but that susceptibility to other entry inhibitors is unaffected."

They added that, "events in vivo can sometimes restore [envelope protein] genotypic and phenotypic heterogeneity by introducing drug-resistant gp41 sequences into heterologous gp120 backgrounds."

These results are encouraging since they suggest that heavily treatment-experienced patients with prior use of enfuvirtide may still benefit from new entry inhibitors currently under development, such as the CCR5 antagonist maraviroc.

Department of Microbiology, University of Pennsylvania, Philadelphia PA; University of California San Francisco, San Francisco CA.

02/09/07

Reference
N Ray, J E Harrison, L A Blackburn, and others. Clinical resistance to enfuvirtide does not affect susceptibility to other classes of entry inhibitors. Journal of Virology. January 24, 2007 [Epub ahead of print].