[14] AMDOXOVIR, A NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITOR, IS ACTIVE AGAINST HIV MUTANTS RESISTANT TO STANDARD NUCLEOSIDE THERAPY

5th International Workshop on HIV Drug Resistance & Treatment Strategies

4-8 June 2001, Scottsdale, Arizona

[TITLE:] AMDOXOVIR, A NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITOR, IS ACTIVE AGAINST HIV MUTANTS RESISTANT TO STANDARD NUCLEOSIDE THERAPY

[AUTHOR(S):] J Jeffrey, K Borroto-Esoda, J Feng, S Fleming, P Furman, J Mewshaw, F Myrick, R Qi, L Rimsky and D Wakefield
Triangle Pharmaceuticals, Durham, N.C., USA
Antivir Ther. 2001;6 Suppl 1:10

The frequency of HIV-1 mutations in response to antiviral therapy and the resulting drug resistance is of major concern. Amdoxovir, the prodrug of dioxolane guanosine (DXG), is currently in Phase I/II clinical development for the treatment of HIV-1. Cell culture assays have shown that HIV-1 mutants resistant to zidovudine (M41L, D67N, K70R, T215Y, K219Q) and lamivudine (M184V) remain sensitive to DXG, with EC₅₀ values of 1.8- and 1.4-fold greater than wild-type. Steady-state kinetic analysis of similar zidovudine and lamivudine recombinant reverse transcriptase (RT) mutants showed only a minor change in the K_{i DXG-TP/}K_{m dGTP} ratio relative to wild-type RT. In vitro passaging of HIV-1 with increasing concentrations of DXG selects RT variants with mutations at K65R or L74V. The K103N mutation, typically associated with non-nucleoside reverse transcriptase inhibitor (NNRTI) therapy, appears to effect a hypersensitive response to DXG in cell culture and kinetic assays. HIV-1 site-directed mutants in LAI and NL4-3 lab strains at L74V alone or in combination with K103N remain sensitive to DXG in cell culture and steady-state assays. HIV-1 site-directed mutants in LAI at K65R alone or in combination with K103N result in an increase in the EC₅₀ of five- to eightfold relative to wild-type. Similar mutants in NL4-3 remain sensitive to DXG. Steady-state analysis of recombinant HXB2 RT mutants at K65R and/or K103N, show less than a threefold change in the K_{i DXG-TP/}K_{m dGTP} ratio relative to wild-type RT. Although LAI, NL4-3 and HXB2 are all from clade B, the specific RT sequence may impact the Scottsdale, Arizona, 4–8 June 2001 5th International Workshop on HIV Drug Resistance & Treatment Strategies 11 level of resistance observed for an anti-HIV-1 compound. The multi-drug resistant mutation, Q151M, produces a 10-fold level of resistance to DXG in cell culture assays. The recombinant Q151M RT mutant shows only threefold increase in the K_{i DXG-TP/}K_{m dGTP} ratio relative to wild-type RT. The combination of K65R and Q151M confers high-level resistance to DXG in cell culture and steady state assays. These in vitro data suggest that amdoxovir may be a useful therapy for treatment-experienced patients.

PRESENTING AUTHOR: J Jeffrey

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