[6] ANTIVIRAL ACTIVITY OF THE NUCLEOSIDE REVERSET FOLLOWING SINGLE ORAL DOSES IN HIV-1-INFECTED PATIENTS

12th International HIV Drug Resistance Workshop

10–14 June 2003, Cabo del Sol, Los Cabos, Mexico

ANTIVIRAL ACTIVITY OF THE NUCLEOSIDE REVERSET FOLLOWING SINGLE ORAL DOSES IN HIV-1-INFECTED PATIENTS

Antivir Ther. 2003; 8:S9 (abstract no. 6)

L Stuyver¹, TR McBrayer¹, RL Murphy^1,2, D Schürmann³, I Kravec³, A Beard¹, RF Schinazi⁴, A De La Rosa¹ and MJ Otto¹
¹Pharmasset, Inc., Tucker, Ga., USA; ²Northwestern University, Chicago, Ill., USA; ³Charité University Hospital, Berlin, Germany; and ⁴Emory University School of Medicine, and Veterans Affairs Medical Center, Atlanta, Ga., USA

BACKGROUND: Reverset (RVT, β-D-2’,3’-didehydro-2’,3’-dideoxy-5-fluorocytidine) is a nucleoside analogue that retains activity against lamivudine- and zidovudine-resistant HIV-1 in vitro. It is being developed under a US IND for the treatment of HIV-1 in nucleoside reverse transcriptase inhibitor (NRTI)-experienced patients.

METHODS: RVT was administered as a single oral dose to antiretroviral treatment-naïve HIV-1-infected males (six per cohort) at doses of 0, 10, 25 or 50 mg as buffered solutions or 0, 50, 100 or 200 mg as enteric-coated tablets. Blood samples, obtained over a 48 h period for pharmacokinetic analysis, were analysed for HIV RNA levels using quantitative realtime RT-PCR.

RESULTS: Viral loads dropped significantly over 48 h with an average reduction of 0.4±0.2 log₁₀ for all dose levels. The antiviral response over the 48 h was not dose-dependent. At the 10 mg dose, a 0.42±0.2 log₁₀ was observed (P=0.005), while at 100 mg a similar effect of 0.44±0.17 were noted (P=0.0007). The dose-independent significant antiviral response was also observed at the 24 h time-point, with an average reduction of 0.11±0.11 (P=0.03). The 12 h time-point was not significantly different from the baseline. The mean plasma C_max values ranged from 1 to 8 μM. A maximal effect of viral inhibition was obtained at the lowest C_max (0.87 mM), which is equivalent to the in vitro EC₉₀ value for wild-type virus. All available viral strains were sequenced in the reverse transcriptase gene before (n=18 strains) and after (n=18 strains) the treatment schedule. Wild-type viral genotype was found in all but one subject who showed at baseline the following genotype: L41+N103+C181+W210+D210, suggesting past exposure to zidovudine (possibly in another host) and non-nucleoside analogues. This subject received the 10 mg, placebo and 25 mg treatment schedule, and showed a 0.61, –0.05 and 0.43 log₁₀ drop, respectively. The viral genotype for all subjects remained unchanged at the end of the treatment schedule.

CONCLUSIONS: RVT reduced the HIV-1 viral load after a single dose by a mean of 0.4 log₁₀ for all doses tested. One subject infected with a mutant virus responded as well as subjects infected with wild-type virus.

PRESENTING AUTHOR: L Stuyver

Download PDF of this abstract.

2003-07-08
6

Copyright © 2003 - International Medical Press Ltd.. Reproduction of this abstract (other than one copy for personal reference) must be cleared through the International Medical Press Ltd. 2-4 Idol Lane, London EC3R 5DD UK.