Resistance

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 than wild-type virus, suggesting that people may continue to get some clinical benefit from T-20 even after the development of resistance.1 Several 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.

An area of gp41 known as HR1 is the site of the development of primary T-20 resistance mutations.2 3 The commonest T-20 resistance mutations have been found at positions 36, 38, 42 and 43 in at least five separate studies.4 5 6 7 8 Recent studies have also found evidence of T-20 resistance mutations in the HR2 region of the gene for gp41, including the mutation S138A.6 7 9 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.

T-20 is active against over 80 HIV strains, over half of which were resistant to the three main drug classes.10 11 12 This suggests that T-20 will not be significantly affected by existing patterns of resistance.13 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.14

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.15

References

  1. Reeves JD et al. Enfuvirtide resistance mutations: impact on human immunodeficiency virus envelope function, entry inhibitor sensitivity, and virus neutralization. J Virol 79: 4991-4999, 2005
  2. Menzo S et al. Genotype and phenotype patterns of human immunodeficiency virus type 1 resistance to enfuvirtide during long-term treatment. Antimicrob Agents Chemother 48: 3253-3259, 2004
  3. Su C et al. Substitutions within HIV gp41 amino acids 36 - 45 are identified as the primary determinants for loss of in vitro susceptibility to enfuvirtide: results of data mining analyses of genotypic changes in gp41 in TORO 1 and TORO 2 that associate with changes in phenotypic susceptibility to enfuvirtide. 13th International HIV Drug Resistance Workshop, Costa Adeje, abstract 162, 2004
  4. Melby T et al. Analyses of virological response and enfuvirtide resistance through 48 weeks in the TORO 1 and 2 studies. 13th International HIV Drug Resistance Workshop, Costa Adeje, abstract 165, 2004
  5. Sista P et al. Characterization of determinants of genotypic and phenotypic resistance to enfuvirtide in baseline and on-treatment HIV-1 isolates. AIDS 18: 1787-1794, 2004
  6. Perez-Alvarez L et al. Long-term monitoring of genotypic and phenotypic resistance to T20 in treated patients infected with HIV-1. J Med Virol 78: 141-147, 2006
  7. Xu L et al. Emergence and evolution of enfuvirtide resistance following long-term therapy involves heptad repeat 2 mutations within gp41. Antimicrob Agents Chemother 49: 1113-1119, 2005
  8. Poveda E et al. Dynamics of enfuvirtide resistance in HIV-infected patients during and after long-term enfuvirtide salvage therapy. J Clin Virol 34: 295-301, 2005
  9. Baldwin CE et al. Emergence of a drug-dependent human immunodeficiency virus type 1 variant during therapy with the T20 fusion inhibitor. J Virol 78: 12428-12437, 2004
  10. Miralles GD et al. Baseline genotype and prior antiretroviral history do not affect virological response to T-1249. Antivir Ther 6: S4, 2001
  11. Sista P et al. The fusion inhibitors T-20 and T-1249 demonstrate potent in vitro antiviral activity against clade B HIV-1 isolates resistant to reverse transcriptase and protease inhibitors and non-B clades. Antivir Ther 6: S3, 2001
  12. Zollner B et al. Primary genotypic resistance of HIV-1 to the fusion inhibitor T-20 in long-term infected patients. AIDS 15: 935-936, 2001
  13. Quinones-Mateu ME et al. Replicative fitness of HIV-1 strains with reduced susceptibility to protease-, reverse-transcriptase- and entry (enfuvirtide)-inhibitors. Thirteenth International HIV Drug Resistance Workshop, Costa Adeje, abstract 61, 2004
  14. Carmona R et al. Natural resistance-associated mutations to enfuvirtide (T20) and polymorphisms in the gp41 region of different HIV-1 genetic forms from T20 naive patients. J Clin Virol 32: 248-253, 2005
  15. Aquaro S et al. Specific mutations in HIV-1 gp41 are associated with immunological success in HIV-1 infected patients receiving enfuvirtide treatment. J Antimicrob Chemother 58: 714-722, 2006
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