AEGiS-15IAC: Potent anti-HIV-1 activity of Reverset™ following 10 days of monotherapy in treatment-naïve individuals.

15th International AIDS Conference

Bangkok, Thailand - July 11-16, 2004

Potent anti-HIV-1 activity of Reverset ™ following 10 days of monotherapy in treatment-naïve individuals.

Int Conf AIDS 2004 Jul 11-16; 15:(abstract no. MoOrB1056)

R L Murphy¹, D Schürmann², A Beard³, R F Schinazi⁴, F Wagner², R Levy⁵, M J Otto³
¹Northwestern University, Chicago, IL, United States; ²ClinicalResearch/Charité-University Medicine, Berlin, Germany; ³Pharmasset, Inc, Tucker, GA, United States; ⁴Emory Univ. Sch. Med., and Veterans Affairs Medical Center, Decatur, GA, United States; ⁵Incyte Corp., Wilmington, DE, United States

BACKGROUND: Reverset (RVT) is a NRTI with specific and potent in vitro activity against wild type HIV-1 and isolates resistant to AZT, 3TC, and other NRTIs. In a single dose Phase 1 study, RVT was well tolerated at doses from 25 to 200 mg with a 0.44 log₁₀ decrease (p< 0.001) in mean HIV plasma RNA levels. Based on these data a 10 day monotherapy study was initiated.

METHODS: Thirty HIV-infected treatment-naïve individuals with CD4+ cell counts >50 cells/mm³ and HIV-1 RNA levels >5,000 copies/ml were enrolled in a 10 day monotherapy qd dose escalation study. RVT (50 mg, 100 mg, or 200 mg) or placebo was administered orally in a double blind manner; plasma samples for HIV-1 RNA and genotyping were obtained predose and during treatment and follow up. 24h pharmacokinetic samples were obtained on day 1 and day 10.

RESULTS: The mean HIV RNA decrease at the end of treatment for the 50, 100, and 200 mg levels was 1.67 ± 0.24 log₁₀, 1.74 ± 0.32 log₁₀, and 1.77 ± 0.23 log₁₀ respectively. Maximum HIV RNA decrease ranged from 1.0 to 2.6 log₁₀. There were no serious adverse events and no dose-limiting toxicity. Plasma PK values were linear with dose on days 1 and 10 of dosing. The C_max values at all doses exceeded the in vitro EC₉₀ for wild type HIV-1 and the Cmax at the 200 mg dose (9.8 + 2.9 muM) exceeded the EC₉₀ for HIV-1 containing TAMS, M184V and K65R. HIV-1 RNA levels slowly returned to baseline during the follow-up period. CD4+ cell counts increased during the treatment phase, but returned to pretreatment levels during the follow-up period.

CONCLUSIONS: RVT was very well tolerated and highly effective in treatment-naïve individuals with up to 1.77 log₁₀ decrease in viral load. The potent antiviral activity and safety in the current study coupled with the in vitro susceptibility of drug-resistant HIV-1 to RVT warrants further investigation. Studies in experienced patients are being initiated.

Keywords: AEGIS, HIV-1, Viral Load, CD4 Lymphocyte Count, Acquired Immunodeficiency Syndrome, Zidovudine, Lamivudine, HIV Seropositivity, Antiviral Agents, Antiretroviral Therapy, Highly Active, Drug Therapy, Combination, In Vitro, Humans, therapy, drug therapy

040711
MoOrB1056