Table 3.
Combination studies of DAAs, cyclosporin A and (S)-CCZ in HCVcc-Luc assay
| Virus type | ID | Antiviral name | MacSynergyII
|
CalcuSyn
|
|||||
|---|---|---|---|---|---|---|---|---|---|
| Synergism LV |
Antagonism LV |
Conclusiona | |||||||
| EC50 CI | EC75 CI | EC90 CI | Conclusionb | ||||||
| HCVcc-Lucc | I | Daclatasvir and cyclosporin A | 2.27 | −0.33 | (+) Minor synergy | 0.93 ±0.31 | 0.67 ±0.22 | 0.49 ±0.18 | (++) Moderate synergy |
| HCVcc-Lucc | J | Telaprevir and cyclosporin A | 2.17 | −0.47 | (+) Minor synergy | 0.99 ±0.31 | 0.98 ±0.28 | 0.97 ±0.29 | () Additive |
| HCVcc-Lucc | K | Boceprevir and cyclosporin A | 1.83 | −0.09 | () Additive | 1.06 ±0.23 | 1.04 ±0.22 | 1.03 ±0.24 | () Additive |
| HCVcc-Lucc | L | Sofosbuvir and cyclosporin A | 7.22 | −0.11 | (++) Moderate synergy | 0.63 ±0.20 | 0.68 ±0.19 | 0.74 ±0.20 | (++) Moderate synergy |
| HCVcc-Lucd | N/A | Daclatasvir and (S)-CCZ | 11.76 | 0 | (+++) Major synergy | 0.31 ±0.18 | 0.43 ±0.21 | 0.63 ±0.26 | (+++) Major synergy |
| HCVcc-Lucd | N/A | Telaprevir and (S)-CCZ | 11.90 | −0.59 | (+++) Major synergy | 0.67 ±0.19 | 0.64 ±0.16 | 0.01 ±0.16 | (+++) Major synergy |
| HCVcc-Lucd | N/A | Boceprevir and (S)-CCZ | 17.00 | −1.21 | (+++) Major synergy | 0.33 ±0.09 | 0.32 ±0.09 | 0.36 ±0.12 | (+++) Major synergy |
| HCVcc-Lucd | N/A | Sofosbuvir and (S)-CCZ | 30.56 | 0 | (+++) Major synergy | 0.16 ±0.03 | 0.20 ±0.04 | 0.27 ±0.05 | (+++) Major synergy |
| HCVcc-Lucd | N/A | 2′-C-methylcytidine and (S)-CCZ | 5.66 | −0.05 | (++) Moderate synergy | 0.36 ±0.09 | 0.34 ±0.07 | 0.35 ±0.07 | (+++) Major synergy |
| HCVcc-Lucd | N/A | Cyclosporin A and (S)-CCZ | 40.80 | −2.16 | (+++) Major synergy | 0.39 ±0.14 | 0.24 ±0.07 | 0.26 ±0.06 | (+++) Major synergy |
Extent of synergy or antagonism in MacSynergyII is defined according to absolute value of log volume (LV) as follows: () additive, LV <2; (+/−) minor, 2≤ LV <5; (++/−−) moderate, 5≤ LV <9; (+++/−−−) major, LV ≥9.
Extent of synergy and antagonism in CalcuSyn is defined as follows: (+++) major synergy, combination index (CI) ≤0.7; (++) moderate synergy, 0.7≤ CI <0.8; (+) minor synergy, 0.8≤ CI <0.9; () additive, 0.9≤ CI <1.1; (−) minor antagonism, 1.1≤ CI <1.3;(−−) moderate antagonism, 1.3≤ CI <3.0; (−−−) major antagonism, CI ≥3.0.
LV (95% confidence level) and CI (±SE) of combinations of direct-acting antivirals (DAAs) with host-targeting agent (HTA) cyclosporin A in HCVcc-Luc.
LV (95% confidence level) and CIs (±SE)of combinations of previously described entry inhibitor (S)-chlorcyclizinc (CCZ) with DAAs and HTA cyclosporin A, in HCVcc-Luc. Raw luciferase values of combinations in triplicate were inputted into MacSynergyII and % inhibition values of combinations at a fixed ratio of concentration of two drugs inputted into CalcuSyn, except those exhibiting >25% toxicity. N/A, not applicable.