681   Safety and Antiviral Activity of Chronic Subcutaneous Administration of T-20 in HIV-1-Infected Children.

J. Church*¹, C. Cunningham², P. Palumbo³, P. Sista⁴, and the P1005 Team.
¹Children's Hosp., Los Angeles, CA;²SUNY Upstate Med. Univ., Syracuse, NY;³New Jersey Med. Sch., Newark, NJ; and⁴Trimeris Inc, Durham, NC.

Background:This is the first pediatric study of safety and antiviral activity of the HIV fusion inhibitor T-20.

Methods:Twelve children 3 to 12 years, on stable antiretroviral therapy >16 weeks, with HIV RNA >10,000c/ ml and no or limited prior treatment with either protease or non-nucleoside reverse transcriptase inhibitors were eligible. Part A evaluated safety and plasma pharmacokinetics following one subcutaneous (SC) and one intravenous (IV) dose. Part B evaluated T-20 bid SC at 30 and 60 mg/m²added on to the stable regimen. After 7 days, background antiretrovirals were changed while T-20 dosing continued.

Results:T-20 was well tolerated. One child discontinued due to aversion to injections, but no child discontinued due to adverse events. Mild to moderate injection site reactions (erythema, induration, pruritus, discomfort) occurred in a majority (8/12) but were usually mild. One grade 3 event of injection site erythema (6 cm) not associated with pain occurred twice in the same child. All other local and systemic events were<grade 2. A dose-limiting toxicity was not identified. T-20 was readily absorbed following SC injection. All patients at 60 mg/m²exceeded the target level of 1.0mg/ml of plasma T-20 at 12 hours. A planned analysis on study day 7 showed 4 subjects who received 30 mg/m²T-20 achieved a mean decline from baseline of 0.84 log and 7 subjects in the 60 mg/m²cohort achieved a mean log decline of 0.97. Three of four subjects given 30 mg/m²and 6 of 7 given 60 mg/m₂achieved a protocol-specified, day 7 milestone of >0.7 log₁₀decline in plasma HIV RNA. Virologic suppression (HIV RNA >1 log₁₀below baseline) continues for 8/9, 7/8 and 6/8 children on study through day 18, week 4 and week 8, respectively. Plasma genotyping of gp41 for 2 children with early virologic failure showed no genetic changes at baseline or week 12 in the previously defined locus that encodes T-20 resistance. Study treatment is ongoing with additional safety and antiviral activity data being collected.

Conclusion:These results indicate that short-term SC dosing with T-20 is safe and well tolerated in children. T- 20 causes potent, rapid suppression of HIV RNA.