4th International Workshop on HIV Drug Resistance & Treatment Strategies Sitges, Spain, 12–16 June 2000

DAPD: A NOVEL INHIBITOR OF HIV AND HBV REPLICATION IS ACTIVE AGAINST DRUG-RESISTANT VIRUSES

Antivir Ther. 2000 Jun 12-16; 5 (Suppl. 3):5 (Abstract 5

PA Furman¹, R Chin², K Borroto-Esoda¹, J Mewshaw¹, B Dent², A Barthalomews² and S Locarnini^2
1Triangle Pharmaceuticals, Durham, N.C., USA; and ²Victorian Infectious Diseases Reference Laboratory, Melbourne, Australia

DAPD, (–)-β-D-2,6-diaminopurine dioxolane, is a nucleoside reverse transcriptase inhibitor with activity against HIV-1 and hepatitis B virus (HBV). DAPD is deaminated in vivo by adenosine deaminase to give (–)β-D-dioxolane guanosine (DXG), which has potent activity against HIV-1 and HBV. EC₅₀ values, deter mined for DXG in PBMCs against several wild-type isolates of HIV-1, ranged from 30 to 290 nM. Against wild-type HBV in LMH cells, 15 μM DAPD reduced the level of extracellular virus by 50%. In HepG2 cells the EC₅₀ for DAPD against HBV when measuring the effect of the compound on relaxed circular DNA, single-stranded DNA and extracellular virus was 9.5, 48 and 6.0 μM, respectively. With HIV, selection of an L74V mutation occurs in vitro following nine passages of HIV-1 in the presence of increasing concentrations of DXG. The L74V mutant exhibited a four-fold increase in EC₅₀ as compared with wild-type HIV-1. Others have described the selection of a K65R mutation following in vitro passage of virus in the presence of DXG (eight-fold increase in EC₅₀). Recombinant viruses and clinical isolates of HIV-1 with mutations at codons 41L, 67N, 69D, 70R, 103N, 184V, 190A, 215Y, 219Q, and G333E, alone or in combination, from patients who failed NRTI and/or NNRTI combination therapies remain sensitive to DXG. Virus with mutations associated with multi-NRTI resistance due to SS or SG insertions between codons 68/69 were sensitive to DXG. A virus containing S68G, Q151M, and T215Y was also sensitive to DXG, but viruses with multiple mutations that included K65R, F116Y, and Q151M showed a 40- to 50-fold increase in EC for DXG. Passaging experiments similar to those performed with HIV are not possible with HBV. Consequently, resistance testing can only be done using site-directed mutants containing mutations known to confer drug resistance in the clinic to lamivudine and/or famciclovir. Using a transient transfection assay, a panel of drug-resistant mutants of HBV (V519L, L526M, M550I, V553I, L526M/M550V, V519L/ L526M, and V519L/L526M/M550V) has been tested in LMH cells for the effect of DAPD on the levels of replicative intermediates from intracellular cores and/or excreted virus. None of these mutants showed any substantial cross-resistance to DAPD. Therefore, DAPD shows promise as a treatment for wild-type and drug-resistant HIV-1 and HBV.

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2000-06-12
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