[2] 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

5th International Workshop on HIV Drug Resistance & Treatment Strategies

4-8 June 2001, Scottsdale, Arizona

[TITLE:] 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

[AUTHOR(S):] P Sista¹, T Melby¹, U Dhingra², N Cammack³, P McKenna⁴, P Dehertogh⁴ and T Matthews¹
¹Trimeris, Durham, N.C., USA; ²Hoffmann-La Roche, Nutley, N.J., USA; ³Roche Welwyn Discovery, Welwyn, Hertfordshire, UK; and ⁴Virco NV, Belgium
Antivir Ther. 2001;6 Suppl 1:3

BACKGROUND: T-20 and T-1249 are peptide fusion inhibitors in clinical trials for the treatment of HIV-1 infection. Due to their novel mechanism of action T-20 and T-1249 are expected to retain antiviral activity against HIV-1 isolates that may be resistant to currently available antiretrovirals (ARVs). In this study, we tested in vitro activity of T-20 and T-1249 against clade B HIV-1 isolates with various patterns of resistance to all currently available ARVs and against HIV-1 isolates from non-B clades.

METHODS: Eighty-six recombinant viral isolates with documented genotypic and phenotypic resistance were selected from the repository at Virco NV and were tested for sensitivity to all approved ARVs, the investigational agent tenofovir (Gilead Sciences) and T-1249 and T-20 using the Antivirogram assay. Twenty nonclade B isolates were also evaluated. We defined resistance as an IC₅₀ increase of >10-fold relative to a reference strain (HIV-1_IIIB) rather than using the phenotypic thresholds from the Antivirogram assay.

RESULTS: Isolates were resistant to a broad range of ARVs and included at least five isolates resistant to each ARV, not including T-20 and T-1249. Resistance to multiple classes of ARVs was present in 59 of 86 isolates, with 32 isolates resistant to two ARV classes and 27 other isolates resistant to three ARV classes. In general, susceptibility to T-20 and T-1249 was moderately enhanced relative to wild-type regardless of ARV resistance. T-20 IC₅₀s ranged from 0.2- to 1.4-fold and T-1249 IC₅₀s ranged from 0.2- to 2.0-fold the IC₅₀ of the reference strain. Activity against the non-B clade isolates was similarly enhanced with sensitivity from 0.4- to 1.2-fold for T-20 and 0.2- to 2.4-fold for T- 1249 relative to HIV-1_IIIB.

CONCLUSION: These results demonstrate that the in vitro antiviral activities of T-20 and T-1249 are independent of resistance to any of the classes of currently approved ARVs. T-20 and T-1249 also demonstrated antiviral activity against non-clade B virus isolates comparable to activity against clade B viruses.

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