Table 3.

Drug–drug interactions of proposed antiviral combinations against coronavirus

Proposed combination (with clinical trial reference if available)	Pharmacodynamic rationale	Drug–drug interactions with level of severity and therapeutic advice [81]	Level of evidence: 1. Clinical trial in coronavirus 2. Retrospective clinical data 3. In vivo animal or in vitro data
Ribavirin + LPV/r [82]	Inhibition of replication PLUS inhibition of RNA synthesis	Increased risk of liver toxicity Level of severity: major Therapeutic advice: monitor for increased liver toxicity	1. Clinical trials: No data 2. Retrospective clinical data : (a) Retrospective matched cohort study for SARS-CoV infection: 41 cases treated with LPV/r + ribavirin vs. 111 historical controls treated with ribavirin alone; better clinical outcome (ARDS and death) at day 21 after onset of symptoms: 2.4% vs. 28.8%; p < 0.001. No difference in outcome reported for early vs. delayed treatment [15] (b) Multicenter retrospective matched cohort study for SARS-CoV infection: 75 cases treated with LPV/r + ribavirin vs. 977 controls treated with ribavirin. Reduction in death (2.3% vs. 15.6%; p < 0.05) and intubation (0% vs. 11%; p < 0.05) was evident only in the subgroup of initial treatment with LPV/r; no significant difference in the late treatment group [38] (c) MERS-CoV infection: post-exposure prophylaxis with ribavirin + LPV/r in 43 healthcare workers resulted in a 40% reduction in the risk of MERS-CoV infection, with no severe adverse events during treatment [83] 3. In vivo animal or in vitro data: In vitro checkerboard assay for synergy on SARS-CoV demonstrated inhibition of the cytopathic effect with a concentration of LPV of 1 μg/ml with ribavirin 6.25 μg/ml when the viral inoculum was < 50 median tissue culture infectious dose [15, 84]
LPV/r + Arbidol [82]	Inhibition of replication PLUS inhibition of RNA synthesis PLUS inhibition of viral entry	No clinical data available CYP3A4 is major pathway of metabolism for arbidol; strong inhibition of CYP3A4-mediated metabolism of arbidol by ritonavir is plausible Level of severity: Unknown Therapeutic advice: Monitor for increased toxicity of arbidol [70]	1. Clinical trials: No data 2. Retrospective clinical data: Case series (n = 4) of mild or severe COVID-19 pneumonia successfully treated with LPV/r + arbidol + Shufeng Jiedo Capsule (traditional Chinese medicine) [85, 86] 3. In vivo animal or in vitro data: No data
Chloroquine + LPV/r	Inhibition of replication PLUS inhibition of viral entry	Increased risk of QTc prolongation (potentially dangerous interaction) Inhibition of CYP3A-mediated metabolism of chloroquine by ritonavir Level of severity: Major Therapeutic advice: Monitor ECG and monitor for increased toxicity of chloroquine if used in combination. Dose reduction of chloroquine might be necessary in case of severe toxicity	1. Clinical trials: No data, but ongoing open-label study currently being undertaken in China (ChiCTR2000029741) [87] 2. Retrospective clinical data: No data 3. In vivo animal or in vitro data: No data
Emtricitabine + tenofovir (Truvada)	Inhibition of RNA synthesis (dual therapy)	No data	1. Clinical trials: No data 2. Retrospective clinical data: No data 3. In vivo animal or in vitro data: No data
Favipiravir + interferon	Inhibition RNA synthesis PLUS immune modulation	No data	1. Clinical trials: Open-label, nonrandomized, comparative controlled study in 80 patients with SARS-CoV-2 infection. Thirty-five patients were treated with FPV plus inhaled IFN-α. Forty-five historic controls received LPV/r plus inhaled IFN-α. Treatment with FPV/IFN led to shorter viral clearance time and improvement in chest imaging at D14. Fewer adverse events were found in the FPV/IFN arm [67] 2. Retrospective clinical data: No data 3. In vivo animal or in vitro data: No data
Emtricitabine + tenofovir (Truvada) +  LPV/r [88]	Inhibition of replication PLUS inhibition of RNA synthesis	Increased tenofovir absorption (i.e. 32% AUC increase; 51% Cmin increase) through P-glycoprotein inhibition Level of severity: Moderate Therapeutic advice: Monitor for tenofovir-associated toxicity	1. Clinical trials: No data 2. Retrospective clinical data: No data 3. In vivo animal or in vitro data: No data
Interferon + ribavirin	Immune modulation PLUS inhibition of RNA synthesis	No data	1. Clinical trials: Ongoing open-label, single-center, prospective, randomized controlled clinical trial in China comparing LPV/r plus IFN-α vs. ribavirin plus IFN-α, vs. LPV/r plus IFN-α plus ribavirin [89] 2. Retrospective clinical data: (a) Multicenter observational study in critically ill patients with MERS-CoV infection. Of 349 MERS-CoV-infected patients, 144 received RBV/rIFN (rIFN-α2a, rIFN-α2b or rIFN-ß1a). Treatment was not associated with a reduction in 90-day mortality or faster MERS-CoV RNA clearance [90] b. Retrospective cohort study of patients with MERS-CoV requiring ventilation support who received supportive care (n = 24) vs. oral ribavirin + pegylated IFN-α2a (n = 20). Treatment with ribavirin + IFN-α2a was associated with significantly improved survival at 14 days, but not at 28 days [91] 3. In vivo animal or in vitro data: Synergistic antiviral effect between ribavirin and type I IFN (i.e. IFN-α [84, 92] or IFN-ß [84, 92, 93]) on SARS-CoV was described in two studies performed in human and Vero cell lines
LPV/r + interferon + ribavirin	Immune modulation PLUS inhibition of RNA synthesis PLUS inhibition of replication	Level of severity: Major Therapeutic advice: Monitor for increased risk for hepatotoxicity (for combination protease inhibitor + ribavirin and protease inhibitor + interferon)	1. Clinical trials: One open-label, randomized, multicenter, phase II trial in Hong Kong in 127 patients with confirmed SARS-CoV2 infection. Eighty-six patients received LPV/r + interferon-β1b + ribavirin combination treatment, and 41 received LPV/r alone. The combination group had a significantly shorter median time from start of study treatment to negative nasopharyngeal swab, and shorter duration of hospitalization than the control group [63] Ongoing open-label, single-center, prospective, randomized controlled clinical trial in China comparing LPV/r plus IFN-α vs. ribavirin plus IFN-α, vs. LPV/r plus IFN-α plus ribavirin [89] 2. Retrospective clinical data: Two case reports, one patient recovered, one patient died during hospital stay due to septic shock [94, 95] 3. In vivo animal or in vitro data: No data
Hydroxychloroquine + azithromycin	Immune modulation PLUS inhibition of viral entry	Increased risk of QTc prolongation (potentially dangerous interaction) Level of severity: Major Therapeutic advice: Monitor ECG	1. Clinical trials: One open-label, non-randomized clinical study in 36 patients with confirmed SARS-CoV2 infection (interim analysis of ongoing trial) [96]. Of 36 patients, 14 received hydroxychloroquine treatment, 6 received hydroxychloroquine/azithromycin combination treatment and 16 were controls. The proportion of patients with negative PCR in nasopharyngeal samples was significantly higher in hydroxychloroquine-treated patients at days 3–6 post-inclusion vs. control patients. If hydroxychloroquine was used in combination with azithromycin, the proportion of patients with negative PCR in nasopharyngeal samples was significantly higher on days 3–6 when compared with patients treated with hydroxychloroquine monotherapy. One open-label, non-randomized clinical study in 80 patients with confirmed SARS-CoV2 infection [97]. Of 80 patients, all expect 2 improved clinically. A rapid fall in nasopharyngeal viral load was observed, with 83% negative at day 7, and 93% at day 8 2. Retrospective clinical data: One retrospective cohort study of 1438 patients hospitalized for COVID-19 in 25 hospitals in metropolitan New York. 735 patients received hydroxychloroquine + azithromycin, 211 received azithromycin alone, 271 received hydroxychloroquine alone, and 221 received neither drug [98] There we no differences in hospital mortality between different treatments One retrospective study of 1061 confirmed SARS-CoV2 patients treated with hydroxychloroquine + azithromycin for at least 3 days in Marseille, France. Good clinical and virological cure was obtained in 973 (91.7%) patients within 10 days [99] Retrospective electronic case record review of 96,032 hospitalized patients. Multivariable Cox proportional hazard model with matched case–control analysis found hydroxychloroquine plus a macrolide resulted in 23.8% mortality vs. 9.3% in controls. Significantly higher mortality was seen with hydroxychloroquine, or chloroquine alone and chloroquine plus macrolide vs. control [11] 3. In vivo animal or in vitro data: No effect of hydroxychloroquine, with or without azithromycin, on viral load in either treatment or prophylaxis in a non-human primate model [100]

LPV/r lopinavir/ritonavir, AUC area under the curve, COVID-19 coronavirus disease 2019, SARS-CoV severe acute respiratory syndrome coronavirus, MERS-CoV Middle East Respiratory Syndrome coronavirus, ARDS acute respiratory disease syndrome, QTc corrected QT interval, ECG electrocardiogram, C_min trough concentration, RNA ribonucleic acid, RBV/rIFN ribavirin + recombinant IFN, PCR polymerase chain reaction, FPV favipiravir, IFN interferon, CYP cytochrome P450, LPV/r lopinavir/ritonavir