Controversies’ clarification regarding ribavirin efficacy in measles and coronaviruses: Comprehensive therapeutic approach strictly tailored to COVID-19 disease stages

Table 6 Studies of all coronavirus outbreaks with statistically significant findings

Regimen tested vs control, Type of study	Severity or disease stage when applied	Significant findings and other very important notes	Outbreak applied
IFN-β + RBV + Lop/r (gr 1) vs Lop/r (gr 2), Randomized, Prospective, Open-label Phase 2[202]	Mild to moderate; No mortality	(1) Shorter time from start of treatment to neg nasopharyngeal swab in group 1 [7 d vs 12 d; HR: 4.37 (1.86-10.24); P = 0.001]. (2) Time to NEWS2 score 0: [4 d vs 8 d; HR: 3.92 (1.66-9.23) P < 0.0001] time to SOFA score 0: [3 d vs 8 d; HR: 1.89 (1.03-3.49); P = 0.041] time to neg viral loads (all specimens): (8 d vs 13 d; P = 0.001). (3) Duration of hospital stay: (9 d vs 14.5 d; P = 0.016). (4) In subgroups when treatment started < 7 d of symptom onset time to NEWS2 score 0: (4 d vs 8 d; P < 0.0001) time to SOFA score 0: (3 d vs 7 d; P = 0.001) time to neg viral loads (all specimens): (7 d vs 13 d; P < 0.0001) Duration of hospital stay: (8 d vs 15 d; P = 0.003]. And (5) Insignificant differences between groups in adverse-effects	COVID-19
RBV + steroids, Retrospective, Multicenter[131]	Moderate to severe 2nd wk Phase 2 all had pneumonia	(1) Time from symptom onset to treatment applied 5.7 d in those uncomplicated vs 7.7 d in those who needed ventilatory support (P = 0.03); (2) Response to treatment in early initiation 28/31 vs 11/19 in late initiation (P = 0.02). Final outcome 31/31 improved/recovered vs 10/19 in late applied (complicated) (P = 0.0001); and (3) Risk factor for complicated outcome was associated with delay starting of treatment	SARS
RBV + Lop/r + steroids vs RBV + steroids (historical), Open-label, Prospective, Non-randomized[87]	Mild to moderate initiation 3.5 d after symptom onset	(1) Development of ARDS or death within 21 d: 1/41 vs 32/111 (P < 0.001); (2) Independent risk factor predicting adverse outcome for the treatment group: aOR 0.07 [(0.01-0.55); P = 0.011]; and (3) Significant lower adverse outcome for those treated early (P < 0.001)	SARS
Peg-IFN-α2α + RBV vs SOC, retrospective[161]	Severely ill with pneumonia	(1) 14-d mortality in treatment gr 6/20 vs 17/24 in control (P = 0.004); (2) 28-d mortality in treated 14/20 vs 20/14 in control (P = 0.054); Loss of difference in 28-d might be explained by high initial APACHE II and SOFA scores and several comorbidities	MERS
RBV + Lop/r + steroids vs RBV + steroids (SOC), Multicenter retrospective matched-cohort (with 643 pts)[140]	Mild to moderate Initiation of RBV 4.5 d and of Lop/r 5.5 d	(1) Less proportion and dose of pulsed Mp in treated gr (P < 0.05); (2) Intubation rate in treated 0% vs 11% (7.7-15.3) in control (P < 0.05); and (3) CFR 0% (0-6.8) in treated vs 15.6% (9.8-22.8) in control (P < 0.05)	SARS
IFN-α + RBV + Lop/r and IFN-α + Lop/r vs SOC, Retrospective[191]	Moderate, hospitalized 7d after symptom onset	Significant correlation of PCR-negative conversion time and length of hospital stay (days) in IFN + lopinavir/ritonavir combined with RBV treatment group (P = 0.0215) and IFN + lopinavir/ritonavir treatment group (P = 0.012)	COVID-19
Several antiviral combinations Retrospective[190]	Severe	(1) The use of two-step clustering and subgroup analyses enabled an in-depth analysis of the effects of single and combination drug therapies. Improvement rate was highest (84.9%) in the group combination of RBV + Lop/r + Umifenovir + Lianhua Qingwen (P < 0.001); (2) Antiviral combination was superior to single or dual agents	COVID-19
IFN + RBV vs SOC, Retrospective[163]	Severe	Patients who survived were more likely to have received IFN + RBV than those who died (P = 0.01)	MERS
RBV + pulsed steroids (PS) (equivalent to Mp > 500 mg/d vs RBV + non-PS (NPS), Multicentre, Retrospective[129]	Severe pneumonia (Phase 2)	(1) Overall trend for chest radiograph scores significantly lower in the PS group than NPS (P = 0.026); (2) The radiographic scores were significantly lower in days 14 and 21 in PS compared to NPS (P = 0.04 and P = 0.04); and (3) No significant difference between the PS and NPS groups in the need of ICU, mechanical ventilation and mortality	SARS
Steroids vs no-steroids, Multicentre, Retrospective[165]	Critically ill pts all in ICU	(1) In marginal structural modelling, steroid therapy was not significantly associated with 90-d mortality but with a delay in MERS RNA clearance (P = 0.005); (2) However pts given steroids were more likely to have one or more comorbidities than without steroids (P = 0.001)	MERS
4 different treatment groups, Prospective, randomized[133]	Moderate	(1) High-dose steroids with a quinolone + azithromycin resulted in significant resolution of pyrexia (P < 0.001), pulmonary infiltrates (P < 0.001), and respiratory improvement (P < 0.001); (2) No particular advantage in using ribavirin was seen (not significant)	SARS
Sofosbuvir/daclatasvir vs RBV SOC: Lop/r + HCQ, Open-label, Parallel trial[199]	Severe	(1) Duration of hospital stay 5 d in Sof/d vs 9 d in RBV arm (P < 0.01); (2) Relative risk of ICU admission 0.36 (0.16–0.81) in Sof/d vs 2.8 (1.2–6.4) in RBV arm (P = 0.01); and (3) Relative risk of death 0.17 (0.04–0.73) in Sof/d vs 5.8 (1.4–25) (P = 0.02)	COVID-19
Multivariate analysis of several treatments, Retrospective[171]	Unclear	(1) IFNs (mainly IFN-β) and MMF were predictors of increased survival in univariate analysis (P = 0.009 and P = 0.019, respectively)	MERS
RBV + steroids within the first 2 d of admission vs no treatment within first 2 d, Retrospective[142]	All cases	The generalized propensity score weighting model predicted that the overall CFR would be the highest (19.2%) if all patients treated with RBV + steroids within 2 d of admission compared with those receiving neither treatment within 2 d of admission (15.4%) with and the difference was marginally statistically significant	SARS
Several therapies evaluated, Retrospective[193]	Moderate to severe	(1) In multivariate analysis for predicting the risk of death in RBV treated was OR 0.477 (0.232-0.982) P = 0.044 and of arbidol 0.28 (pneumonia onset) (0.126-0.625) P = 0.002; (2) in multivariate analysis of parameters associated with death in pts with cardiovascular disease and cardiac injury from the disease, RBV had an OR 0.208 (0.070-0.618) P = 0.005 and arbidol P = 0.006	COVID-19
Several therapies evaluated, Meta-analysis[88]		(1) Anti-coronavirus interventions significantly reduced mortality RR 0.65 (0.44-0.96; I2 = 81.3%), remarkably ameliorate clinical improvement RR 1.62 (1.11-2.36; I2 = 11%) without manifesting clear effect on virological eradication, incidence of ARDS, intubation and adverse effects; (2) The combination of RBV + steroids remarkably decreased mortality RR 0.43 (0.27-0.68); (3) The combination of RBV + Lop/r + steroids showed tendency of lower mortality whereas the combination of IFN + steroids demonstrated higher mortality tendency; and (4) The Lop/r-based combination showed superior virological eradication and radiographic improvement with reduced rate of ARDS	COVID-19, SARS, MERS
Treatment side-effects
RBV[88]	RBV can induce more bradycardia, anemia, and transaminitis		COVID-19, SARS, MERS
IFN-α + RBV[161]	Reduction in Hb 4.32 g/L vs 2.14 g/L (P = 0.002)		MERS
RBV[89]	Hemolytic anemia was significantly associated with high-dose RBV (P = 0.005) and prolonged hospital stay (P = 0.001). Also hypocalcemia, hypomagnesemia		SARS
Antiviral combinations[201]	Gastrointestinal side-effects (vomiting, diarrhea) more significant (P < 0.01) in the combination of IFN-α + RBV + Lop/r than in IFN-α + RBV and the IFN-α + Lop/r groups. The combination of RBV + Lop/r should not co-administered to COVID-19 pts simultaneously		COVID-19

ARDS: Acute respiratory distress syndrome; CFR: Case fatality rate; HCQ: Hydroxychloroquine; HR: Hazard ratio; ICU: Intensive care unit; IFN: Interferon; Lop/r: Lopinavir/ritonavir; MERS: Middle East respiratory syndrome; MMF: Mycophenolate mofetil; OR: Odds ratio; RBV: Ribavirin; RR: Relative risk.