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Drug Susceptibility Profile of OBP-601, a novel NRTI,
Using a Comprehensive Panel of NRTI and/or NNRTI Resistant Viruses
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Reported by Jules Levin
15th CROI 2008
J. Weber 1, J. Weberova 1, A.C. Vazquez 1, Y.Urata 2, T. Matsuda 2, R.A. Shafer 3, E.J. Arts 4, and M.E. Qui–ones-Mateu 1
1 Diagnostic HYBRIDS, Inc. Cleveland, OH, USA; 2 Oncolys BioPharma, Tokyo, Japan; 3 Stanford University, Stanford, CA, USA; 4 Case Western Reserve University, Cleveland, OH, USA

Background: Despite the relative success of antiretroviral therapy, emergence of drug resistant HIV-1 variants continues to be the major cause for treatment failure. OBP-601 (4'-Ed4T) is a novel nucleoside analog with potent anti-HIV-1 activity and limited cellular toxicity, which has a unique in vitro resistance profile. Here we evaluated (i) the ability of OBP-601 to inhibit the replication of multi-drug resistant viruses and (ii) its potential use in combination therapy.
Methods: A panel of 40 3'Gag/PR/RT-recombinant viruses were generated using PCR products from clinical samples harboring selected sets of NRTI resistance mutations (e.g., NAM, TAM41, TAM67, M41l+V118I, K65R, L74V, and Q151M, plus K103N + M184V). These viruses were employed in drug susceptibility assays to test the activity of OBP-601 alone or in combination with AZT, d4T, ABC, TDF, 3TC, EFV, NVP, LPV, ATV and darunavir. Viral replication was quantified using luciferase expression and/or an in-house RT assay, and 50% (IC50) inhibition concentration were determined. Antiviral isobolograms were calculated for the combination studies.
Results: OBP-601 susceptibility of recombinant viruses carrying wild type 3'Gag/PR/RT sequences ranged from 0.76 to 5.80 µM in our in vitro system, slightly lower than the parental compound d4T (1.57 to 6.06 µM).
The anti-HIV-1 activity of OBP-601 was reduced in most viruses carrying NAM (5- to 10-fold), TAM41 (0.3- to 4.3-fold), and TAM67 (1.6- to 7.8-fold) resistance mutations, together with K103N + M184V.
Interestingly, viruses carrying the Q151M substitution were hypersusceptible to OBP-601 (0.1- to 0.2-fold), even in the presence of K65R (0.3- to 1.3-fold). More important, OBP-601 showed strong (AZT, EFV) to moderate (ABC, TDF, NVP) synergistic interaction with different antiretroviral drugs in wild type viruses. Similar results were obtained with 3TC, EFV, and ABC in viruses carrying M184V, K103N, and Q151M, respectively.
Conclusions: The unique resistance profile of OBP-601, its effectiveness against drug-resistant viruses (e.g., carrying the Q151M complex), and the synergistic effect with other RTI (in both wild type and drug resistant viruses) warrant further investigation for its potential use in combination therapy against HIV-1.

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