As with all other anti-HIV drugs, strains of HIV that are resistant to T-20 (enfuvirtide, Fuzeon) may emerge after a period of treatment. The emergence of drug-resistant strains coincides with a fall in the effectiveness of the drug.

Resistance mutations to T-20 emerged rapidly during early tests. However, there is evidence from test tube studies that T-20 mutations do not reduce the virus’s susceptibility to other experimental entry inhibitors. Furthermore, HIV that is resistant to T-20 is less fit that wild type virus, suggesting that people may continue to get some clinical benefit from T-20 even after the development of resistance^[1]. Recent studies have found that, as with other anti-HIV drugs, failing to combine T-20 with other active drugs can lead to resistance rapidly, within less than eight weeks in most cases^[2].

An area of gp41 known as HR1 is the site of the development of primary T-20 resistance mutations^[3][4]. The commonest T-20 resistance mutations have been found at positions 36, 38, 42 and 43 in at least five separate studies^{[5][6][7][8][9]}. Recent studies have also found evidence of T-20 resistance mutations in the HR2 region of the gene for gp41, including the mutation S138A^[10][11][12]. These mutations change the shape of the gp41 protein that allows HIV to fuse with CD4 T-cells even in the presence of T-20.

Studies have found that T-20 is active against over 80 HIV strains, over half of which were resistant to the three main drug classes^[13][14][15]. This suggests that T-20 will not be significantly affected by existing patterns of resistance^[16]. However, as the use of T-20 becomes more common, patients are becoming infected with strains of HIV that are already resistant to the drug^[17].

There is also evidence that the mutation V38A/E in gp41 results in higher levels of CD4 cell count recovery, in response to treatment with T-20. Conversely, the same study found a link between the mutations Q40H and L45M, and impaired immune reconstitution^[18].