Great natural diversity in susceptibility to fusion inhibitors has been noted. Considerably more viruses from treatment-naive patients show reduced susceptibility to fusion inhibitors in vitro compared to other drug classes. This variability in susceptibility is likely to be more pronounced for agents targeting gp120 and its interactions, since regions of gp120 are extremely variable. This means that there will be differences in susceptibility within and between individuals.

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. Resistance to T-20 is usually associated with mutations at positions 36 through 45 on a region of the gp41 envelope gene, known as the first heptad repeat (HR1) region^[1][2]. There is a low genetic barrier to ENF resistance and failure with the emergence of genotypic and phenotypic resistance due to just one or two mutations may occur within weeks if ENF is not used with a sufficiently potent background regimen.

Baseline analysis of participants in key T-20 trials TORO 1 and 2 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^[3].

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 ^[4]. 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 ^[5].