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5th International Workshop on HIV Drug Resistance & Treatment Strategies4-8 June 2001, Scottsdale, Arizona |
BACKGROUND: T-1249 is a peptide fusion inhibitor rationally designed as a follow-on compound to the related peptide, T-20. In laboratory studies, T-1249 has demonstrated activity against a broad range of HIV-1 isolates. We evaluated the in vivo antiviral activity of T-1249 in a Phase I/II dose escalation study.
METHODS: Sixty-three fusion inhibitor-naïve, HIV-infected subjects with plasma HIV RNA =5000 copies/ml received T-1249 monotherapy by subcutaneous injection for 14 days at doses ranging from 6.25 to 50 mg/day, on a once or twice daily regimen. Multivariable linear regression analysis was conducted to determine the prognostic significance of baseline and treatment factors on the antiviral activity of T-1249.
RESULTS: The patient population was heavily experienced to antiretroviral agents (ARVs) (mean 10.3 agents; SD 3.2). Ninety-eight percent had received nucleoside reverse transcriptase inhibitors (NRTIs), 89% had received non-nucleoside reverse transcriptase inhibitors (NNRTIs) and 97% had received protease inhibitors (PIs), with a mean exposure to five, two and three agents, respectively. Baseline genotyping (variable wash-out period) showed that 48% of patients had relevant mutations to all three classes of antiretroviral agents. No patient demonstrated the presence of mutations in the HR1 region known to confer resistance to T-20 during the study. Suppression of HIV RNA occurred in a dose-dependent manner. On day 14, the median change from baseline ranged from –0.10 (6.25 mg/day) to –1.40 (50 mg/day) log10 copies/ml. Regression model analysis revealed that antiviral activity was only significantly associated with dose (P<0.0001) after adjusting for duration of prior antiretroviral exposure, duration of the wash-out period, the number or type of mutations in RT or protease, or the presence of mutations to all three drug classes.
CONCLUSION: These results indicate that T-1249 provides dose-related suppression of plasma HIV RNA. The antiviral activity of T-1249 in vivo is unaffected by prior exposure to available ARVs or by multiple resistance mutations to NRTIs, NNRTIs or PIs.
PRESENTING AUTHOR:
010604
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