Table 2.
Comparison of combinations of DAAs of different classes in HCVcc-Luc and Con1b replicon assays and combination study of DAAs of same class in HCVcc-Luc assay
| Virus type | ID | Antiviral name | MacSyncrgy II
|
CalcuSyn
|
|||||
|---|---|---|---|---|---|---|---|---|---|
| Synergism LV |
Antagonism LV |
Conclusiona | |||||||
| EC50 CI | EC75 CI | EC90 CI | Conclusionb | ||||||
| HCVcc-Lucc | A | Daclatasvir and telaprevir | 0.13 | −1.95 | () Additive | 1.47 ±0.20 | 1.34 ±0.16 | 1.23 ±0.15 | (−) Minor antagonism |
| HCVcc-Lucc | B | Daclatasvir and boceprevir | 3.61 | 0 | (+) Minor synergy | 1.01 ±0.14 | 1.05 ±0.13 | 1.08 ±0.14 | () Additive |
| HCVcc-Lucc | C | Sofosbuvir and telaprevir | 4.1 | −1.27 | (+) Minor synergy | 1.00 ±0.24 | 1.00 ±0.23 | 1.01 ±0.23 | () Additive |
| HCVcc-Lucc | D | Sofosbuvir and boceprevir | 0.42 | 0 | () Additive | 1.26 ±0.17 | 1.03 ±0.12 | 0.85 ±0.10 | () Additive |
| HCVcc-Lucc | E | Daclatasvir and sofosbuvir | 2.11 | 0 | (+) Minor synergy | 0.75 ±0.26 | 0.57 ±0.18 | 0.44 ±0.14 | (+++) Major synergy |
| Con1b repliconc | A | Daclatasvir and telaprevir | 0.4 | −0.94 | () Additive | 1.50 ±0.12 | 1.49 ±0.12 | 1.48 ±0.13 | (−) Minor antagonism |
| Con1b repliconc | B | Daclatasvir and boceprevir | 1.39 | −1 | () Additive | 1.26 ±0.09 | 1.28 ±0.10 | 1.29 ±0.12 | (−) Minor antagonism |
| Con1b repliconc | C | Sofosbuvir and telaprevir | 0.02 | −4.83 | (−) Minor antagonism | 1.49 ±0.36 | 1.26 ±0.34 | 1.07 ±0.34 | (−) Minor antagonism |
| Con1b repliconc | D | Sofosbuvir and boceprevir | 0 | −1.36 | () Additive | 1.17 ±0.09 | 1.14 ±0.09 | 1.12 ±0.11 | (−) Minor antagonism |
| Con1b repliconc | E | Daclatasvir and sofosbuvir | 19.08 | −0.03 | (+++) Major synergy | 0.45 ±0.16 | 0.49 ±0.16 | 0.54 ±0.19 | (++) Moderate synergy |
| HCVcc-Lucd | F | Daclatasvir and daclatasvir | 3.06 | −1.77 | (+) Minor synergy | 1.30 ±0.44 | 1.11 ±0.36 | 0.95 ±0.35 | () Additive |
| HCVcc-Lucd | G | Telaprevir and boceprevir | 1.77 | 0 | () Additive | 1.17 ±0.17 | 1.18 ±0.15 | 1.18 ±0.14 | (−) Minor antagonism |
| HCVcc-Lucd | H | Sofosbuvir and 2′-C-methylcytidine | 0.16 | −0.47 | () Additive | 0.83 ±0.16 | 0.89±.0.15 | 0.95 ±0.16 | (+) Minor 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 different classes of direct-acting antivirals (DAAs) and with HCVcc-Luc and Con1b rcplicons.
LV (95% confidence level) and CIs (±SE) of combinations of DAAs of the same class in HCVcc-Luc. Additivity is defined as a combinatorial effect equal to the sum of each drug’s effect alone. Raw luciferase values of all 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.