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Session 96
Poster Abstracts New Antiretroviral Agents: New Classes Wednesday, 1:30 - 3:30 pm Hall A |
Background: Because
of increasing viral resistance and persistent viral replication despite the use
of reverse transcriptase and protease inhibitors, HIV-1 attachment and entry
inhibitors represent a promising new class of antiretrovirals.
TAK-652 is an orally bioavailable, small-molecule
Methods: Using
peripheral blood mononuclear cells (PBMC) infected with 2 HIV-1 R5 clinical
isolates, we evaluated antiviral interactions between TAK-652 and zidovudine, lamivudine, efavirenz, indinavir, and enfuvirtide (T-20). Single drugs or combinations of drugs
were added to each well, using a fixed ratio among drugs and serial dilutions. Cultures
were maintained for 7 days. HIV-1 p24 antigen was measured in supernatant fluid
harvested at the end of culture. Results were analyzed using the median-effect
principle and are expressed as combination indices (CI) with CI values < 0.9
= synergy, between 0.9 and 1.1 = nearly additive effects, and > 1.1 =
antagonism.
Results: No
toxicity was seen in PBMC at TAK-652 concentrations as high as 100 nM. The mean IC50 value for TAK-652 against
HIV-1(R5-01) was 0.17 nM and against HIV-1(R5-18) was
0.44 nM. CI values are shown in the table.
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Combination
Indices for TAK-652 and Other Antiretrovirals at
Various Inhibitory Concentrations against R5-01 |
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Drugs |
IC
50 |
IC
75 |
IC 90 |
IC
95 |
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Zidovudine |
0.94 |
0.81 |
0.72 |
0.66 |
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Lamivudine |
0.92 |
0.79 |
0.72 |
0.69 |
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Efavirenz |
1.13 |
0.99 |
0.87 |
0.80 |
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Indinavir |
1.06 |
0.99 |
0.94 |
0.91 |
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Enfuvirtide |
1.05 |
1.04 |
1.03 |
1.03 |
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Combination
Indices for TAK-652 and Other Antiretrovirals at
Various Inhibitory Concentrations against R5-18 |
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Drugs |
IC
50 |
IC
75 |
IC 90 |
IC
95 |
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Zidovudine |
0.86 |
0.80 |
0.74 |
0.71 |
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Lamivudine |
0.59 |
0.57 |
0.56 |
0.56 |
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Efavirenz |
1.17 |
1.02 |
0.91 |
0.86 |
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Indinavir |
1.09 |
0.92 |
0.79 |
0.72 |
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Enfuvirtide |
0.62 |
0.35 |
0.20 |
0.13 |
Combination index (CI) < 0.9 = synergy;
CI < 1.1 = near additivity,
CI > 1.1 = antagonism
*Mean of 2 to 4
experiments ± SD
Conclusions: The favorable in vitro
anti-HIV drug interactions observed between existing antiretroviral agents of
several classes and TAK-652 suggest that further clinical evaluation of this
R-5 inhibitor is warranted.
Keywords: CCR5 inhibitor; synergy; antiretroviral combinations
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