Background: Because of increasing viral resistance and persisting viral replication despite the use of reverse transcriptase and protease inhibitors, attachment/entry inhibitors represent a promising new class of antiretrovirals. TAK-220 is an orally bioavailable small molecule CCR5 antagonist with anti-HIV activity in the nanomolar range. We evaluated the anti-HIV-1 interactions between TAK-220 and various reverse transcriptase, protease and fusion inhibitors in vitro.

Methods: Using peripheral blood mononuclear cells infected with 2 HIV-1 R5 clinical isolates, we evaluated antiviral interactions between TAK-220 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 = additive effects and > 1.1 = antagonism.

Results: No toxic effects were seen in PBMC at TAK-220 concentrations up to 100 nM. The mean IC50 value against HIV-1(RM) was 4.37 nM and against HIV-1(JC) was 10.50 nM. CI values are shown in the table below.

 

TAK-220 +	Mean Combination Indices  against HIV-1 (RM) at Various Inhibitory Concentrations
	IC 50	IC 75	IC 90	IC 95
Zidovudine	1.02	0.69	0.52	0.44
Lamivudine	0.96	0.70	0.52	0.43
Indinavir	1.26	0.94	0.78	0.71
Efavirenz	0.73	0.58	0.49	0.47
T-20	0.77	0.62	0.54	0.50

 

 

 

TAK-220 +	Mean Combination Indices  against HIV-1 (JC) at Various Inhibitory Concentrations
	IC 50	IC 75	IC 90	IC 95
Indinavir	0.77	0.64	0.63	0.66
Efavirenz	0.81	0.70	0.69	0.70

 

Conclusions: The favorable in vitro anti-HIV drug interactions observed between existing antiretroviral agents of several classes with TAK-220 suggest that further clinical evaluation of this R-5 inhibitor is warranted.