Great natural diversity in susceptibility to fusion inhibitors has been noted. A much more substantial number of viruses from treatment-naive patients show reduced susceptibility to fusion inhibitors in vitro compared to other drug classes, where susceptibility tends to be tightly clustered around the mean. In the case of T-20 (enfuvirtide, Fuzeon), up to a quarter of isolates appear either hypersusceptible to T-20 or to have reduced susceptibility compared to wild-type.

This variability in susceptibility is likely to be more pronounced for agents targeting gp120 and its interactions, since regions of gp120 are hyper-variable. This means that there will be differences in susceptibility within and between individuals.

Baseline analysis of TORO 1 and 2 participants found that 15% had a polymorphism at position N42S in gp41, but this was not associated with reduced susceptibility to T-20. The mutations V38A, V38V/A, G36D, N43D, V38M were associated with mean reductions in susceptibility of 15- to 42-fold. N43N/D was associated with a mean fivefold reduction in susceptibility (Greenberg 2003).

Research into coreceptor inhibitors and resistance is ongoing. There is evidence from a study of maraviroc that resistance to one CCR5 inhibitor does not necessarily produce resistance to all CCR5 inhibitors (Westby 2005). In regard to drugs which target the CXCR4 co-receptor, there is evidence that AMD070 has antiviral effect on virus which has been previously exposed to AMD3100 (Schols 2005).

References

Derdeyn C et al. Sensitivity of HIV-1 to fusion inhibitors is modulated by coreceptor specificity and involves distinct regions of gp41. First IAS Conference on HIV Pathogenesis and Treatment, Buenos Aires, Argentina, abstract 75, 2001.

Greenberg ML et al. Baseline and on-treatment susceptibility to enfuvirtide seen in TORO 1 and TORO 2 to 24 weeks. Tenth Conference on Retroviruses and Opportunistic Infections, Boston, abstract 141, 2003.

Labrosse B et al. Baseline susceptibility of primary human immunodeficiency virus type 1 to entry inhibitors. J Virol 77: 1610-1613, 2003.

Lalezari JP et al. Enfuvirtide, an HIV-1 fusion inhibitor, for drug-resistant HIV infection in North and South America. New England Journal of Medicine. N Engl J Med 348: 2175-2185, 2003.

Schols D et al. Multi-drug resistant HIV-1 is sensitive to inhibition by chemokine receptor antagonists. Twelfth Conference on Retroviruses and Opportunistic Infections, Boston, abstract 545, 2005.

Westby M et al. Structurally related HIV co-receptor antagonists bind to similar regions of CCR5 but have differential activities against UK-427,857-resistant primary isolates. Twelfth Conference on Retroviruses and Opportunistic Infections, Boston, abstract 96, 2005.