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BILR 355: New NNRTI
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Reported by Jules Levin
Antiviral profile of BILR 355 BS against a large panel of clinical isolates with mutations conferring resistance to currently available non-nucleoside
reverse transcriptase inhibitors (NNRTI)
PR Bonneau1, PA Robinson2, Y Lie3, N Parkin3, R van Leeuwen4 and R Bethell1
1Boehringer Ingelheim (Canada) Ltd Research & Development,
Laval, QC, Canada
2Boehringer Ingelheim Pharmaceuticals Inc, Ridgefield, CT, USA
3ViroLogic Inc, South San Francisco, CA, USA
4International Antiviral Therapy Evaluation Centre (IATEC),
Amsterdam, The Netherlands
BACKGROUND: BILR 355 BS is a novel non-nucleoside reverse transcriptase inhibitor (NNRTI) with potent antiviral activity against wild-type HIV-1 and
recombinant viruses with ≥1 mutations conferring phenotypic resistance to the currently available NNRTIs (nevirapine, efavirenz, delavirdine). To further characterize its antiviral profile, BILR 355 BS was tested against several clinical isolates associated with resistance to first-generation NNRTIs.
METHODS: Two sets of clinical isolates were tested with BILR 355 BS and first-generation NNRTIs at ViroLogic using the PhenoSense methodology which
constructs recombinant viruses by incorporating the amplified PR and RT regions of patient viruses into a luciferase-containing retroviral vector. Set A consisted
of 225 randomly selected NNRTI-resistant viruses with a fold-change (FC) ≥10 against at least one of the currently available NNRTIs (inclusion criteria). Set B
consisted of 139 isolates selected from the 2NN clinical study (most being baseline and time of first-failure matched isolates).
RESULTS: BILR 355 BS had an EC50 value of 6 nM in the PhenoSense assay against the reference NL4-3 HIV-1 wild-type strain. Within set A, 141/225 (63%)
of the isolates had FC ≦10 toward BILR 355 BS (22% for efavirenz, 1.7% for nevirapine). Of those isolates with only one NNRTI-associated mutation, 67/76
(88%) had FC ≦10 to BILR 355 BS compared with 52/74 (70%) and 22/75 (31%) with 2 or ≥3 mutations respectively. Within the 2NN isolates (set B), 47/50
(94%) of those with only one NNRTI mutation had FC ≦10 to BILR 355 BS (58% for efavirenz, 16% for nevirapine) compared with 12/21 (57%) and 2/3 for
those with two or ≥3 NNRTI mutations respectively.
89% (108/121) of the single and double mutant isolates containing the K103N mutation had FC ≦10 (both sets combined). Consistent with earlier observations,
the majority of isolates with FC >10 had ≥3 NNRTI-associated mutations or contained either the infrequent V106A or Y188L mutation.
CONCLUSIONS: The susceptibility of clinical isolates to BILR 355 BS was tested. Results show that it maintains potent antiviral activity against a majority of isolates containing mutations associated with NNRTI treatment failures, supporting its continued development for treatment of NNRTI-resistant HIV.
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