Copyright
©The Author(s) 2021.
World J Clin Cases. Jul 6, 2021; 9(19): 5135-5178
Published online Jul 6, 2021. doi: 10.12998/wjcc.v9.i19.5135
Published online Jul 6, 2021. doi: 10.12998/wjcc.v9.i19.5135
Table 1 Ribavirin’s antiviral activity and clinical uses
| Type of virus | Antiviral activities and clinical uses |
| DNA viruses | HSV1, 2[8]; CMV at higher concentrations[9]; Several adenovirus serotypes[10] |
| RNA viruses | HCV non-genotype 1: RBV + PEG-IFN; although, none of the drugs seems to have direct effect on virus. RBV enhances the pSTAT4 and IFN-γ response of NK cells to IFN-α stimulation[11]; however, in later studies, RBV was found to induce significantly more G-to-A and C-to-U transitions, a genetic signature that is indicative of RBV-induced mutagenesis[12,13]. HEV: In transplant recipients treated for HEV, RBV ensures a sustained virological response[14]. Pre-treatment HEV polymerase mutations and de novo mutations under ribavirin did not have a negative impact on HEV clearance[15]. RSV: RBV is a well-tolerated option to treat RSV infections in immunocompromised patients[16,17]. β-Coronaviruses, comprising MHV-3, SARS-CoV, MERS-CoV, and SARS-CoV-2 (see text for extensive data). Influenza virus (A and B)[18]; Paramyxoviruses[19]; Measles (see text); Mumps[20]; Parainfluenza types 1, 2, 3[21]; Rhinoviruses exhibit variable sensitivity[22], while combination treatment was effective in patients with hypogammaglobinemia[23]. HIV (in vitro)[24], WNV (flavivirus): RBV lowers RNA levels and reduces cytopathogenicity in vitro[25]. Poliovirus and coxsackie B virus are insensitive[9], Hemorrhagic fever viruses, including arenaviruses, bunyaviruses, hantaviruses, filoviridae (Marburg and Ebola viruses) and the Flaviviridae (yellow fever and dengue virus). RBV is effective against most of these major pathogens, except for Ebola, Marburg, yellow fever, dengue, and Machupo virus[26]. Arenaviruses: LCMV inhibition is also mediated through a decrease in GTP levels[27]. Crimean-Congo hemorrhagic fever: RBV is the only antiviral treatment with decreased fatality rates[28,29]. Lassa fever and Hantaan virus have been tested and showed potential susceptibility in vitro and/or in animal models[30,31] |
Table 2 Ribavirin multimodal mechanisms of action with distinct examples
| Type | Mechanism |
| Direct | |
| 1 | Inhibition of RdRp-RNA synthesis |
| Direct interaction with RTP. RTP has been reported to competitively inhibit the influenza virus RNA polymerase, with respect to ATP and GTP, whereas RMP has no such observable effect[32]; however, for HCV, there are conflicting data regarding the impact of RBV on the RdRp, with reports of both no direct inhibition[33] as well as observations that RBV-containing RNA templates can cause a significant blockage of RNA elongation[34] | |
| Shown for Influenza A, La Crosse virus and for the key HIV polymerase, reverse transcriptase[24,32,35] | |
| Influenza virus: For cells treated with either RBV or methotrexate (a purine synthesis inhibitor that decreases intracellular concentrations of purines), the loss of polymerase activity at low concentrations of nucleotide is the culprit[36] | |
| Hantaan virus: The observed increase in RBV-5’-triphosphate supports the direct interaction and inhibition of the virus RdRp[37,38] | |
| 2 | Increasing viral mutation rates through the misincorporation of RBV into the genome, leading to population extinction[39] |
| RBV triphosphate is incorporated into the viral RNA by poliovirus polymerase, where it templates cytidine and uridine equally efficiently[40]. It has been suggested that RBV enhances viral mutagenesis, leading to error catastrophe by incorrect substitution of RTP for GTP[34,40,41] into viral RNA as most viral RdRps lack proofreading capability; although, this mechanism has been disputed for some viruses[42]. For example, for poliovirus, a 9.7-fold increase in mutagenesis following RBV treatment resulted in 99.3% loss in infectivity[40]. RTP is incorporated into the viral RNA by poliovirus by poliovirus polymerase, where it templates cytidine and uridine equally efficiently[40]. It has been suggested that RBV enhances viral mutagenesis, leading to error catastrophe by incorrect substitution of RTP for GTP[34,40,41] into viral RNA as most viral RdRps lack proofreading capability; although, this mechanism has been disputed for some viruses[42]. For example, for poliovirus, a 9.7-fold increase in mutagenesis following RBV treatment resulted in 99.3% loss in infectivity[40]. RTP is incorporated into the viral RNA by poliovirus polymerase, where it is mutagenic, since it templates cytidine and uridine equally efficiently[9]. Unlike GTP, RTP has ambiguous base-pairing capacity and can form two hydrogen bonds with uridine triphosphate or cytidine triphosphate with equal efficiency[40], leading to a subsequent increase in G-to-A and C-to-U single nucleotide variations throughout the entire HCV open reading frame[43]. Recent in vivo studies indicate that similar RBV-induced mutagenesis occurs in HEV[44] | |
| HCV: Initial studies showed no mutagenic effects, while in later results a mutagenic activity was indeed observed[45-47] | |
| LCMV: Along with the inhibition of IMPDH enzyme, a mutagenic activity also occurs[27] | |
| 3 | Interference with formation of the 5’ cap structure of viral mRNA (capping activity) |
| This is probably due to competitive inhibition of both guanyltransferase and methyltransferase capping enzymes | |
| mRNAs contain extensive modification on the 5´ end (known as the “five prime cap”), often utilizing guanine which is methylated in the 7-position, as this is essential for the stability and efficient translation of mRNA[39]. Thus, RNA capping has major secondary impact on the translation of both viral and host cell mRNAs. Interestingly, RTP reportedly acts as a competitive inhibitor for the capping of mRNAs, subsequently leading to impaired translation[48] by forming a covalent RMP-capping enzyme intermediate in place of the normally observed GMP-enzyme intermediate[49] | |
| Thus, virus which do not form capped mRNA are relative insensitive to RBV | |
| Mutants of Sindbis virus with an altered guanyltransferase demonstrate acquired resistance to RBV[50] | |
| Indirect | |
| 1 | Inhibition of IMPDH by RBV-5’-monophosphate |
| RBV is a structural analogue of guanosine and acts as a potent competitive inhibitor of the enzyme IMPDH by RMP, leading to reduced GMP biosynthesis by diminution of the conversion of inosine monophosphate to XMP and resulting in the depletion of intracellular GTP[51]; this process is reversible in vitro by the addition of exogenous guanosine[52]. XMP can then be aminated to GMP by the GMP synthase enzyme. GMP is further converted to guanine metabolites, such as GTP and dGTP, essential precursors for RNA and DNA synthesis, respectively. This inhibition of IMPDH may occur even at relatively low RBV concentrations (10 μmol/L)[53] and leads to marked changes in the balance of the GTP pool in cells, with subsequent major impact on the host cell and viral gene expression as well as on viral replication[54-58]. This effect may be reversible in vitro by the addition of exogenous guanosine[59] | |
| HEV replication in vitro: MPA (an IMPDH inhibitor) has the same antiviral effect as RBV, which can be neutralized by the addition of guanosine[60] | |
| HCV: RBV acts through the inhibition of IMPDH, since the addition of guanosine negates this effect[45] | |
| LCMV: Inhibition is also mediated through a decrease in GTP levels[27] | |
| 2 | Immunomodulatory effects of RBV |
| Initially, a possible effect on T-cell subset balance was suggested[40,41]. RBV was also shown to inhibit lymphocyte proliferation, possibly due to the depletion of GTP which is essential for proliferating T-cells[61,62]. In vitro, IL-2 and IL-4 production was affected at lower RBV concentrations than IFN-γ production, suggesting a differential effect on Th1 and Th2 lymphocytes[63]. RBV administration in mice infected with influenza virus significantly attenuated respiratory immune responses as well as secretory and total IgA mucosal responses[64]. Affects T-cell subset balance[61,62]. Ameliorates spontaneous autoimmune disease in mice[65]. Inhibits lymphocyte proliferation due to depletion of GTP, which is essential for proliferating T-cells[61,66]. Enhances Th-1 over Th-2 responses or up-regulates the IFN-stimulated response element[63,67]. Clinical HCV studies have demonstrated that RBV monotherapy down-regulates the expression of IFN-stimulated genes in addition to reducing systemic concentrations of liver enzymes[68], and similarly lowered systemic concentrations of IP-10 (also known as CXCL10) associated with successful therapeutic outcome[69] in spite of only modest impact on viral levels | |
| In an animal model[67] for acute and chronic liver disease induced by the first coronavirus, many years before SARS emerged, MHV-3 was examined. MHV-3 has been the main model in studies on coronavirus replication and pathogenesis. Resistance to MHV-3 is associated with predominant Th1 response, the production of IFNs, neutralizing antibodies, and cytotoxic T cells. Viral infection of macrophages leads to a marked inflammatory response, including sustained production of TNF, IL-1, and procoagulant Fg12 prothrombinase and is associated with a Th2 cellular immune response and production of non-neutralizing antibodies. In hepatocellular necrosis (viral, toxins, etc.) resident macrophages (Kupffer cells) are activated and release a number of inflammatory mediators, including TNF, IL-1, proteolytic and enzymes, and inactivation of these macrophages prevents hepatic necrosis. RBV has minimal inhibitory effects on replication of MHV-3 in vitro, even at high concentrations. However, at concentrations achievable in vivo, it almost totally inhibits the production of the proinflammatory mediators TNF, IL-1 and procoagulant activity in macrophages in vitro[67]. RBV diminishes IL-4 production both by the Th1/Th2 lines as well as by the MHV-3 specific Th2 cell line, while it has no effects on IFN-γ production by Th1 cells, thereby preventing the shift to a Th2 response. The beneficial effect of RBV may be related to its ability to markedly reduce macrophage activation, thereby inhibiting the production of proinflammatory mediators from virally-activated macrophages; in addition, it diminishes Th2 cytokine production, while preserving Th1 cytokine production. RBV activates p53 by stimulating the mTOR protein and promoting the interaction between mTOR and p53. Activated p53 stimulates the transcription of IFN regulatory factor 9 and subsequently enhances IFN signaling (plasmids of lentiviruses that express either scrambled sequence or short-hairpin RNA against mTOR[70]. Furthermore, RBV-induced activation of mTOR and p53 enhances IFN-dependent signaling for the IFN-α/RBV combination treatment[71]. RBV stimulates the ERK1/2 pathway and subsequently promotes p53 activity, which at least partly contributes to the enhanced antiviral response of IFN-α plus RBV against HCV[71]. Regarding which is the predominant RBV antiviral mechanism, it is likely that for most viruses, RBV does indeed exert pleiotropic effects. However, a trend in the last decade has been to explore mutagenesis as the primary antiviral effect against RNA viruses, while clinical studies could determine whether mutagenesis occurs in vivo and how to optimize this activity in a therapeutic context[26] | |
Table 3 Severe acute respiratory syndrome coronavirus, Middle East respiratory syndrome coronavirus and severe acute respiratory syndrome coronavirus-2 in vitro, in vivo (animal), in silico study results focused on ribavirin treatment
| Ref. | Isolates | Cell line | Compounds studied | Results (EC50 μg/mL INFs IU/mL, unless stated otherwise) | Researchers’ conclusion | Comment |
| SARS | ||||||
| Cinatl et al[113], 2003 | FFM-1, FFM-2 | Vero | 6-azauridine | → 16.8 | Glycyrrhizin inhibits SARS-CoV replication; search for therapeutic compounds against SARS will be greatly facilitated by establishing growth of SARS-CoV in human cells | Utilization of a resistant to RBV cell line (Vero E6 cell line, Pitfall 1); however, authors noticed the need for growth in human cell lines |
| Pyrazofurin | → 4.2 | |||||
| MPA | → > 50 | |||||
| RBV | → > 1000 | |||||
| Glycyrrhizin | → 300 | |||||
| Tan et al[114], 2004 | Singapore isolate | Vero E6 | IFN-β1b | → 10000 | RBV is inactive against SARS-CoV. IFNs exhibit antiviral activity | Utilization of Vero E6 cell line, Pitfall 1 |
| IFN-αn3 | → 10000 | |||||
| RBV | → 10000 | |||||
| IFN-β1b + RBV | → No synergistic inhibitory effect | |||||
| Ströher et al[112], 2004 | Tor2, Tor3 Tor7, Tor684 | Vero E6 | RBV | → No SARS susceptibility up to concentrations of 2000 μg/mL | RBV alone is unlikely beneficial; combination with IFN-α2b should be evaluated | Utilization of Vero E6 cell line, Pitfall 1 |
| IFN-α2b | → Substantial inhibitory effect at concentrations ≥ 1000 | |||||
| Chu et al[87], 2004 | HKU-39849 | Fetal Rhesus Kidney-4 | RBV | → 50 | Cytopathic effect of SARS was inhibited by Lop and RBV | First different cell line used than Vero → positive results |
| Lop | → 4 | |||||
| Saijo et al[115], 2005 | HKU-39849Frankfurt-1 | Vero E6 | Mizoribine | → IC50 3.5 | Mizoribine and RBV possess an inhibitory effect. Discrepancy between studies for RBV could be attributed to the duration of incubation times of the cells in the presence of RBV | First study with positive results for RBV in Vero cell lines. Totally correct conclusion for discrepancies between studies |
| RBV | → IC50 20 | |||||
| Chen et al[116], 2004 | 10 SARS-CoV isolates | Vero E6, fRhk-4 | IFN-α | → 5000 (fRhk-4), 19.5 (Vero) | Pre-incubation 16 h with IFNs enhanced activity. RBV and Lop were less active in the Vero cell line. IFNs + RBV was the most effective combination | The study includes Pitfall 1, the rest are ok |
| IFN-β1α | → 2000 (fRhk-4), 10.6 (Vero) | |||||
| RBV | → 50-100 (fRhk-4), > 200 (Vero) | |||||
| Lop | ||||||
| IFNs + RBV synergism | → 2-4 (fRhk-4), 4-8 (Vero) | |||||
| Morgenstern et al[117], 2005 | FFM1, 6109 | Vero, CL14, CaCo2, PK-15, HPEK, MA-104, | RBV | → > 1000 (Vero), → 9.4 (MA-104), → 2.2 (PK-15), → 5.2-8.2 (human cell lines) | IFN-β + RBV combination inhibits SARS-CoV replication in drastically reduced concentrations | The study includes Pitfall 1, the rest are ok |
| IFN-β + RBV | → 10-fold lower RBV concentration,→ 50-2000-fold, lower IFN concentrations | |||||
| Synergism | → Combination index 0.45 | |||||
| Barnard et al[118], 2006 | SARS Urbani strain | Vero 76, Vero E6 MA-104 CaCo2, BALB/c mice | RBV | → 270, EC90 = 560 | RBV, like other IMPDH inhibitors, may enhance viral replication in lungs. Four days after cessation of therapy, RBV promoted pro-inflammatory cytokine production, although 3 d after RBV administration inhibited pro-inflammatory cytokine production in mice by significantly reducing IL-1α, IL-5, MCP-1 and GM-CSF. Authors concluded that their data do not support the use of RBV or other IMPDH inhibitors for SARS treatment | The only study with such high RBV’s EC50 in human CaCo2. It is not explained why animals were treated only for 3 d with RBV showing good results and then it was ceased for 4 d, just to confirm the disease worsening with untoward outcomes. Also Pitfall 1 is included in the study |
| RBV | → 1253 | |||||
| RBV | → EC90 = 225 | |||||
| RBV | → EC90 = 4100 | |||||
| Shah et al[119], 2010 | VSV, SeV | BHK21, BSRT7, HeLa, A549, 4T1, HEp2, Vero | RBV | Both viruses have the ability to initiate infection in all cell line tested. RBV effectively inhibited VSV in BSRT7, HeLa and HEp2 cells even at the lowest tested drug concentrations. However, RBV had a surprisingly mild effect on VSV in Vero and A549 cells even when used at 1000 μg/mL concentration with a somewhat intermediate effect in 4T1 cells. A similar pattern of RBV-resistance was shown for SeV in BHK21, Vero and A549, suggesting that cellular rather than virus-specific factors determine the dramatic differences in their response to RBV. RBV treatment even at 1000 μg/mL concentration did not produce any statistically significant decrease in cell viability in any of the tested cell lines. The development of cell-based resistance to RBV treatment via decreased RBV uptake can greatly limit RBV activity. RBV uptake was inhibited in most cell lines at both lower and higher NBMPR concentrations, a specific inhibitor of ENT via ENT1, 2, previously shown to be primarily responsible for RBV import into the cells. Dramatic variations were observed in the long-term accumulation of RBV in different cell types. Importantly, it correlated with the antiviral efficacy of RBV in the tested cell lines. All the three RBV-resistant cell lines, BHK21, A549, and especially Vero showed markedly decreased levels of RBV accumulation suggesting that such differences in the intracellular RBV metabolism may be responsible for the natural cell resistance to antiviral RBV treatment. Act-D an inhibitor of DNA-primed RNA synthesis, was able to revert the antiviral effect of RBV against several RNA viruses, with two proposed mechanisms (1) the stabilization of cellular GTP levels, and (2) inhibition of RTP production. ActD had a clear neutralizing effect on RBV in most cell lines. ActD treatment did not inhibit RBV uptake, demonstrating that the observed reversal of RBV antiviral action was not due to interference of ActD with RBV uptake. The observed resistance of VSV and SeV to RBV in Vero, BHK21, and A549 was not due to the generation of RBV-resistant mutants in these cells. Even when the cells were pretreated with RBV starting 24 h before infection, a little effect of RBV on viral replication in RBV-resistant cells was observed, ruling out any possibility of virus adaptation to RBV. In addition, when VSV was passed by 10 to 15 times in HeLa, BSRT7, and BHK21 cells in the presence of sub-inhibitory RBV concentrations, no viral adaptation to RBV was ever observed. RBV uptake in all tested cell lines after 15min treatment showed that no one of the tested cell lines was defective to RBV uptake. In long-term RBV accumulation in cells after 16 h or 24 h treatment four cell lines sensitive to RBV showed significantly higher levels of RBV accumulation compared to RBV-resistant BHK21, A549, and Vero. Vero cells had a particularly low accumulation which explains the highest resistance to RBV. This long-term accumulation is dependent on the cellular metabolism of RBV. Neutral RBV molecule can be transported freely in and out of a cell via ENTs but once it is phosphorylated, negative charged RMP, RDP, or RTP are trapped inside the cells. A good illustration of the difference between the RBV uptake and its long-term accumulation is RBV hyper-accumulation in erythrocytes resulting in hemolytic anemia in some RBV-treated patients. Similarly to nucleated cells, RBV is transported into erythrocytes via ENTs and converted into RMP, RDP, and RTP. However, unlike nucleated cells, erythrocytes lack the phosphatases needed to hydrolyze RMP/RDP/RTP into RBV. Exogenous guanosine had a clear (almost 100%) neutralizing effect on RBV in BHK21, A549 and Vero cells, which are already highly resistant to RBV. However, very little effect was observed on the RBV activities in RBV-sensitive cells, especially HeLa, 4T1, and HEp-2 cells. Unlike guanosine, ActD was able to effectively neutralize RBV in all tested cell lines. Authors hypothesized that RBV antiviral activity in these cell lines depends not only on the depletion of GTP pool (can be restored by guanosine) but also on the successful 5’-phosphorylation of RBV into RMP/RDP/RTP. At the same time they suggested that RBV acts in RBV-resistant cells types primarily via depletion of GTP pool due to insufficient amounts of phosphorylated RBV molecules in these cells, explaining why the effect of RBV can be completely reversed in these cell lines by guanosine | ||
| Smith et al[120], 2013 | MHV-A59 SARS-CoV (Urbani strain) | Murine astrocytoma DBT Vero E6 | CoVs contain the largest known RNA genome and encode an array of 16 viral replicase proteins, including a 3' to 5' exoribonuclease domain, ExoN, within the non-structural protein 14 Nsp14. The exon is the first identified proofreading enzyme for an RNA virus and functions together with other CoV replicases to perform the crucial role of maintaining CoV replication fidelity. In DBT cells, MHV-ExoN+ viruses were resistant to 10 μM of RBV, while MHV-ExoN- virus titers decreased by~200-fold following treatment with same RBV concentrations, a surprising finding because at least 10-fold higher RBV concentrations are required to inhibit poliovirus and chikongunya viruses. Furthermore, they determined the sensitivity of ExoN + and ExoN-at a low multiplicity of infection. Unexpectedly, multi-cycle replication of ExoN-viruses in the presence of RBV was indistinguishable from single-cycle replication. Using qRT-PCR, researchers determined that ExoN-genomic RNA was dose-dependently reduced by RBV, while ExoN + RNA was unaffected. Extracellular addition of guanosine restored ExoN-titers, even in presence of RBV. These data indicate that the antiviral activity of RBV against MHV-ExoN-viruses is occurring, at least in part, through decreasing viral RNA synthesis and inhibition of IMPDH, while the presence of ExoN activity is capable of preventing RBV inhibition of CoV replication. However, the increased sensitivity of MHV-ExoN-to RBV could result from the impairment of undefined functions of ExoN during replication, particularly during RNA synthesis | |||
| MERS | ||||||
| Chan et al[153], 2013 | hCo-EMC | MDCK | 1280 drugs screened | IFN-β1b and MPA should be considered in the treatment trials of MERS. IMPDH inhibitors inactive in Vero cell line | A combination of IFNs with RBV was not tested. Coexistence of Pitfall 1 | |
| MPA | → 0.17 | |||||
| RBV | → 9.99-41.45 | |||||
| IFN-α2b | → 6709.8 | |||||
| IFN-β1a | → 480.5 | |||||
| IFN-β1b | → 17.6 | |||||
| Vero | RBV, MPA | → Inactive | ||||
| Falzarano et al[155], 2013 | hCoV-EMC/2012 | Vero, LLC-MK2 | RBV | → 41.45 (Vero), 16.33 (LLC) | Lower sensitivity to RBV for LLC than Vero cells. RBV + IFN-α2b, when combined, the inhibitory concentrations drops to ranges achievable in humans | Coexistence of Pitfall 1. Very significant outcomes for IFN + RBV combination |
| IFN-α2b | → 58.08 (Vero), 13.26 (LLC) | |||||
| Combination | 8-and 16-fold decrease in the inhibitory concentration as either treatment alone | |||||
| Falzarano et al[156], 2013 | hCoV-EMC/2012 | Rhesus macaque | IFN-α2b + RBV | Treated animals showed improved clinical parameters, no dyspnea, little evidence on X-ray. They also showed reduced systemic and local pro-inflammatory markers, significant reduction in viral genome copies in lung tissues and less severe histopathological changes compared to untreated | They suggested IFN-α2b + RBV should be considered for early intervention therapy in MERS. The hedgehog signaling pathway was identified as a putative contributor to decreased lung damage | Very significant results for the early IFN-α2b + RBV administration |
| Hart et al[154], 2014 | Hu/Jordan- N3/2012 (Jordan strain) | Vero E6 | MPA | → IC50 = 2.87 | INF-β and MPA or a combination should be considered for MERS-CoV infected patients | The study involves Pitfall 1 |
| RBV | → > 250 | |||||
| IFN-β | → IC50 = 1.37IFN-β antiviral activity was 16- 41-, 83-, and 117-fold higher than those of IFN-α2b, IFN-γ, IFN-type I and IFN-α2a, respectively | |||||
| Chan et al[157], 2015 | EMC/2012 | Common marmosets | MMF | → A single dose did not improve and might have worsened MERS infection | IFN-β and Lop/r are effective against MERS infection in common marmosets. They concluded that potentially effective combinations that should be evaluated could be RBV and IFN- β1b and/or Lop/r. Although high doses of RBV are limited by side-effects, low-dose RBV combined with IFN- β1b and/or Lop/r may be synergistic | RBV was not tested, but surprisingly the authors discuss its combination with IFN-β1b and/or Lop/r as potentially effective |
| Lop/r | → Improved clinical, radiological, pathological features, and lowered lung and other tissue viral load | |||||
| IFN-β1b | → Less severe disease and lower tissue viral loads | |||||
| SARS–CoV–2 | ||||||
| Computational studies | ||||||
| Kandeel et al[183], 2020 | The first available crystal structure of COVID-19 proteins is the main protease, M-pro, and belongs to the translated NSPs together with the papain-like protease Pl-pro | 20 drugs | Molecular modelling, virtual screening, docking, sequence comparison statistics and phylogenetics of the COVID-19 M-pro were investigated. Phylogenetic analysis showed a 96.08% identity between COVID-19 and SARS-CoV M-pros, while low identity of 51.61% was detected for COVID-19 and MERS-CoV. In the Schrodinger glide docking module, curcumin was found to be a strong inhibitor of SARS M-pro and the tested compounds’ relative docking scores were calculated compared with the docking score for curcumin. RBV and telbivudine were ranked at the 2nd and 3rd positions respectively, where RBV was shown to form two hydrogen bonds with M-pro. Given the high similarity of SARS and COVID-19 M-pros, RBV as well as telbivudine might be of value in treating COVID-19 | |||
| Elfiky et al[184], 2020 | NSPs such as RdRp (nsp12) are crucial enzyme in the life cycle of the RNA viruses. Docking experiments were performed using the optimized COVID-19 and SARS RdRps | Anti-polymerase drugs against HCV | The active site of RdRp is highly conserved, representing two successive aspartate residues protruding from a beta-turn structure, making them surface accessible through the nucleotide channel (which free nucleotides can pass through). Sofosbuvir and RBV are nucleotide derivatives competing with physiological nucleotides for the RdRp active site, and form 7 and 13 H-bonds respectively. Sofosbuvir, RBV and remdesivir can be used against the nCoV-2019, having promising results. GTP derivatives may be used as specific inhibitors against COVID-19 | |||
| In vitro studies | ||||||
| Choy et al[187], 2020 | BetaCoV/ Hong Kong VM20001061/2020 | Vero E6 | RBV | → CPE 500 mmol/L | Remdesivir, Lop, and emetine inhibit SARS-CoV-2 replication. RBV and favipiravir showed no inhibition. Combinational therapy may provide better clinical benefits | Pitfall 1 |
| Remdesivir | → CPE 25 μmol/L | |||||
| Lop | → CPE 25 μmol/L | |||||
| Favipiravir and others | → CPE > 100 μmol/L | |||||
| Wang et al[186], 2020 | nCoV-2019 BetaCoV/ Wuhan/ WIV04/2019 | Vero E6 | RBV | → 109.5 μmol/L | Remdesivir and chloroquine are highly effective in the control of 2019-nCoV | Pitfall 1 |
| Favipiravir | → 61.88 μmol/L | |||||
| Nafamostat | → 22.5 μmol/L | |||||
| Nitazoxanide | → 2.12 μmol/L | |||||
| Remdesivir | → 0.77 μmol/L | |||||
| Chloroquine | → 1.13 μmol/L | |||||
Table 4 Treatment recommendations for viral hemorrhagic fevers and coronavirus outbreaks
| Ref. | Number of patients/RBV commencement after symptom onset in d | Treatment protocol/dosing regimens | Outcomes | Authors’ conclusions | Comments |
| Viral hemorrhagic fevers | |||||
| Borio et al[123], United States | Recommendations for viral hemorrhagic fevers | Intravenous: ld of 30 mg/kg (max of 2 g) once, followed by 16 mg/kg (max of 1 g per dose), qid × 4 d, followed by 8 mg/kg (max of 500 mg per dose) tid × 6 d | Peros: Ld 2000 mg → 1200 mg/d in two divided doses (if weight > 75 kg) or 1000 mg/d in two doses (400-600 mg) if weight ≤ 75 kg for 10 d | RBV is the only potentially effective drug available for selected hemorrhagic fevers | There seems to be a discrepancy between the iv and the oral posology |
| SARS-CoV | |||||
| Koren et al[91], Canada | Recommendations by the Canadian Society for Clinical Pharmacology | Recommended RBV dosage adjusted to Crcl: If Crcl > 60 mL/min → 400 mg tid iv × 3 d, then 1200 mg bid × 7 d | Adverse events: Dose-dependent anemia; electrolyte disturbances (hypocalcemia, hypomagnesemia) CNS effects; teratogenic potential | Until more information becomes available, RBV will continue to be recommended at least in a subset of sicker patients | Deals mostly with RBV adverse-effects |
| MERS-CoV | |||||
| Chong et al[158], Korea | Antivirals should be considered as soon as possible after diagnosis | High-dose: 2.0 g po Ld → 1.2 g tid po × 4 d → 600 mg tid po × 4-6 d (adjusted to Crcl). Intermediate-dose: 2.0 g po. Ld → 10 mg/kg po tid × 10 d. IFN-α2a 180 μg/wk sc × 2 wk. Lop/r 400/100 mg po bid × 10 d | No data available. Side-effects: RBV → hemolytic anemia. Peg-IFN → myeloid dysfunction | The Guidelines focus on antiviral drugs to achieve effective management of MERS treatment | OK |
| SARS-CoV-2 | |||||
| National Health Commission of the People’s Republic of China: the COVID-19 Diagnosis and Treatment Guide 7th Edition[188], China | RBV 500 mg iv bid or tid × 10 d Use in combination with Lop/r or IFNs | IFΝ-α 5 MU nebulization bid. Lop/r 400/100 mg bid 10 d. Chloroquine 500 mg po bid × 7 d. Umifenovir 200 mg po tid × 10 d | Lp/r: Monitor closely for nausea/vomiting. Chloroquine: Avoid in cardiovascular disease. Concurrent use of three or more antiviral agents is not recommended | OK | |
Table 5 Severe acute respiratory syndrome coronavirus, Middle East respiratory syndrome coronavirus and severe acute respiratory syndrome coronavirus-2 clinical studies focused on ribavirin treatment
| Ref. | Total no patients/ Patients treated with RBV | Days from symptoms onset to RBV initiation, as mean | Dosing regimen/Duration | Other treatments | Outcome | Side effects | Authors’ conclusions | Comments |
| SARS-CoV clinical studies | ||||||||
| Hsu et al[124], Singapore | 20/14 | 10-14 | 20 mg/kg tid orally | Antibiotics, Oseltamivir | 6 intubated, 3 died | No | No obvious response to RBV, some deteriorated in spite of its use | Too late RBV initiation when disease is already in Phase II (Pitfall 2) |
| Chiang et al[125], Taiwan | 4 | 4-9 | 1 g/d orally | Levofloxacin,IVIG, If severe hypoxia developed → Mp 2 mg/kg/d | No mortality | No | Beneficial preliminary results. Despite early use of steroids in SARS may prolong its natural course, in rapid progression and severehypoxia it may prevent from further lung injury by cytokine storm | Despite the low administered RBV dosing (Pitfall 3), satisfactory outcome |
| Poutanen et al[126], Canada1 | 10/7 | Unclear | 2 g ld → 1 g qid × 4 d → 0.5 g tid × 4-6 d | Antibiotics, Oseltamivir No steroids | RBV → 1 died. 1 in ICU but improving and 5 recovered | No | Pts treated with RBV improved but due to an array of therapeutics. The effect of RBV is unclear | The time gap between illness onset and RBV initiation is not reported |
| Avendano et al[127], Canada | 14 | 4.6 d stayed at home | 2 g ld → 1 g qid × 4 d → 0.5 g tid × 4-6 d | Levofloxacin 8 pts received pulsed MP | All developed dyspnea, abnormal X-ray. None intubated. Full recovery | 9 pts hemolysis (days 4-6), 2 pts transfuse. 8 pts discontinued RBV but 2 pts relapsed, restarted RBV→ Recovered | RBV was associated with hemolysis that might have increased morbidity in 9 pts. No death, No intubation. 3 pts with severe hypoxia treated with iv steroids | Very promising combination of RBV + Levofloxacin + Pulsed Mp when hypoxia occurred |
| Tsang et al[128], Hong Kong | 10 | 9.6 ± 5.4 d | 8 mg/kg tid iv or 1.2 g tid orally | Antibiotics Steroids iv in all | 2 pts → died, 8 improved | No | Combination of RBV + high dose steroids coincided with clinical improvement | Late RBV administration (Pitfall 2) |
| Lee et al[129], Hong Kong | 138 | When fever persisted > 48 h or Leukopenia/ Thrombo- cytopenia occurred | 1.2 g tid po. If worsening 0.4 g tid iv | Antibiotics, Oseltamivir, Ps 1 mg/kg. If worsening 2-3 Mp pulses 0.5 g iv daily | 5 pts → died, 32 pts in the ICU. 19 pts intubated, 76 pts were discharged. | No | The similarity of disease imaging with BOOP and of histologic features with ARDS, prompted authors to use RBV + steroids. The majority of the cohort responded to the combination | CMR = 3.6%. The time-gap between the disease onset and the therapy initiation was not reported. Nevertheless, outcomes were satisfactory |
| Ho et al[130], Hong Kong | 72 | 4d | 8 mg/kg iv tid × 7 d → 1.2 g tid po, altogether 10-14 d | Antibiotics, Steroids in 3 different regimens: Hc or Mp at dosages similar to treatment of acute severe asthma or pulsed Mp as in ARDS | Day-21 as assessment for short-term outcome. 4/72 died, 12 admitted to ICU, 6 intubated | No | Initial use of pulsed Mp appears to be a more safe and efficacious steroid regimen when compared with regimens of lower dosages | CMR = 5.5% Satisfactory results for RBV + steroids when RBV early applied |
| Peiris et al[131], Hong Kong1 | 75 | As soon as SARS diagnosis was established | 8 mg/kg iv tid × 14 d | Antibiotics, Hc tailing regimen (200 mg iv tid × 10 d then tapered), Mp pulses if worsening 0.5 g iv/d for 2-3 doses | At day 21, 5 died (6.7%). Convalescence at home 27 pts, 43 pts remained in hospital of whom 13 in ICU (17%) and totally 19 pts intubated | No | Higher mortality than that reported from Lee et al[129] (6.7% vs 3.5%). The clinical progression, shifting radiological findings, and the inverted V viral-load profile suggest that worsening in week 2 is related not to uncontrolled viral replication but rather to immunopathological damage | The time-gap from symptoms onset to treatment initiation is unclear |
| Peiris et al[132], Hong Kong | 50 monitored for 12 d | 6.7 d | 8 mg/kg tid iv 7-10 d | Antibiotics, Hc 200 mg tid tailed off | 6 pts received treatment before ICU admission all recovered. 31 uncomplicated pts recovered. From 19 complicated pts 1 died | No | Complicated cases were associated with underlying diseases and delayed use of RBV and steroid treatment. CMR = 2% | Ok |
| Booth et al[133], Canada | 144/126 | First 48 h of hospitalization | 2 g ld → 1 g qid × 4 d → 0.5 g tid × 3 d | Antibiotics Ster 40%, Hc 20-50 mg/d × 10 d | 103 pts discharged. 8 pts died (6 with DM, 1 with cancer) | 49% decrease in Hb > 2 g/dL. 40% transaminitis. 14% bradycardia | Poor outcome was associated with RBV treated pts but it was not significant | Despite unclear time gap between disease onset and RBV initiation, it seems that RBV alone (no Mp pulses, low steroid regimen in only 40% of pts), might not exert a clear benefit (Pitfall 4) |
| Zhao et al[134], China3 | 190/40. pts allocated to 4 groups | Not reported | group A: 0.4-0.6 g/d iv | Antibiotics | 2 pts died. 3 intubated. The rest followed group D → improved | No | Early use of high- dose steroids with quinolone + azi gave the best outcome. No advantage from RBV | Unclear time-gap, too low RBV dosing (Pitfall 3). RBV treatment alone (Pitfall 4) |
| So et al[135], Hong Kong | 31 pts → 1 recovered on antibiotics | 5.5 d | RBV 400 mg iv tid × 3 d then 1200 mg bid orally × 10-14 d | Broad-spectrum antibiotics, Mp 1 mg/kg tid × 5 d then 1 mg/kg bid × 5 d. When worsening pulsed Mp 0.5 g iv. Then Ps 0.5 mg/kg bid × 5 d orally | 17 pts showed rapid response. 13 achieved improvement with step-up or pulsed MP. None intubated. No mortality | No | Protocol provided satisfactory outcomes | No mortality reported |
| Lau et al[136], Hong Kong | 88 pts → 3 recovered on antibiotics/ 68 | 5.8 d | So et al[135] treatment protocol applied | So et al[135] treatment protocol applied | 18 pts required ventilation. 30 pts needed Mp pulses. All-cause mortality for pts aged < 60 was 0% (0/76) and 3/12 (25%) in aged > 60. CXRs of all survivors were significantly clearer in discharge | No | The standard treatment protocol of RBV + steroids and pulsed Mp resulted in satisfactory outcomes | Total CMR = 3.4% Ok |
| Dwosh et al[137], Canada | 15 pts, treatment data only for 1 case | Post-intubation 9 d | 2 g ld iv → 1 g qid × 4 d → 0.5 g tid × 6 d | Mp 40 mg × 2 | Successfully extubated | No | No treatment conclusions | Late RBV initiation (Pitfall 2) |
| Sung et al[138], Hong Kong | 138/94 | 3 d (0-11) to admission. RBV started after 48 h | 2.4 g ld orally → 1.2 g tid. If dyspnea → 400 mg tid iv | Antibiotics Ps 0.5-1 mg/kg. If dyspnea → Hc 100 mg tid. Mp pulses for 3 d (up to 3 g) | 25/94 pts responded toRBV. Mp in 107 non-resp. → 88.8% success. 15 pts died (mortality 10.9%) | Modest degree of anemia in 59% | RBV’s role is doubtful in treatment. Pulsed Mp associated with improvement | RBV alone or associated with low dose steroids seems insufficient for SARS Phase 2 (Pitfall 4). Possibly RBV is insufficient when applied in respiratory failure |
| Leong et al[139], Singapore | 229/97 compared to a group of pts who did not receive RBV on day 6 | 6.4 d. Duration 5.6 d. Doctor- dependent RBV use | Oral 1.2 g tid iv 400 mg tid | Insufficient data | Mortality 10.3% vs 12.9% in control. HR of death for RBV 0.78 (P = 0.53). When adjusted for steroids HR = 1.03 (P = 0.93) | No difference in side effects | Use of RBV alone does not seem to confer any benefit | Late use of RBV (Pitfall 2), uneven groups, doctor-dependent use of RBV (Pitfall 5). RBV alone seems insufficient (Pitfall 4) |
| Leung et al[140], Hong Kong | 1755/1467 met SARS criteria/ 1416 received RBV | On symptom onset: 25 pts. 1-3 d: 480 pts. 4-6 d: 499 pts. ≥ 7 d: 412 pts | Not reported | Not reported | 302 died → mortality 17.2%. CFR of 25 pts: 4.0%, of 480 pts: 11.1%, of 499 pts: 10.0%, of 412: 12.5%, of 51 pts treatment not prescribed: 29.4% | No side-effects reported | The timing of RBV administration did not seem to statistically significantly influence outcome | Authors explain their finding that it possibly results from residual confounding or insufficient power to detect a difference given that most pts were treated (Pitfall 5) |
| Knowles et al[89], Canada | 110 pts focused on RBV side-effects | Not reported | High-dose RBV(total > 20 g): 2 g ld → 1 g qid × 4 d → 0.5 g tid × 3 d; Low-dose RBV: 0.4 g iv tid × 4 d → 1.2 g po bid × 7 d | Antibiotics 50% steroids | 61% hemolytic anemia. 28% transfused with ≥ 1 U of RBCs. A significant decrease (> 2 mg/dL) in Hb was seen at 6.8 d after RBV started, and reached a nadir at 13 d. Anemia associated with higher RBV doses (P = 0.005) and prolonged hospital stay (P = 0.001). 35/76 pts developed hypomagnesemia, 32/62 pts developed hypocalcemia. Teratogenic effect: it is recommended that 15 half-lives (6 mo) is required to complete washout after RBV discontinuation | In contrast to HK experience where RBV associated side effects have not been detailed, their comparable RBV doses suggest that associated side effects are frequent. The benefits of RBV use may not outweigh the risk of side effects with negative economic consequences on hospitals | No outcome results for the 110 pts were reported | |
| Chan et al[141], Hong Kong4 | 75 pts compared with matched cohorts of 643 and 343 pts | As soon as SARS diagnosis established. Lop/r 5.5d and 1 d after RBV. Rescue therapy: 18 d | 2.4 g oral ld → 1.2 po tid or 8 mg/kg tid × 10-14 d | Lop/r 400/100mg bid × 10-14 d. 1 group received it as initial treatment and a 2nd as rescue. In addition, tailing steroids regimen × 21 d and pulsed Mp | Lop/r as initial therapy CRF 2.3% vs 15.6%(P < 0.05), intubation rate 0% vs 11% (P < 0.05). As rescue no difference | No | Early Lop/r initiation in addition to standard treatment protocols (Ho, So) showed significantly beneficial outcomes | Combination of early RBV with Lop/r and steroid regimens with pulsed Mp when needed showed statistically significant results in intubation and mortalityrates. Ok |
| Chu et al[87], Hong Kong5 | 111pts historical controls compared to 41 pts treated with RBV + Lop/r | Once diagnosis was established for RBV. For Lop/r initial treatment group it was started at a median of 3.5 d while in the rescue group at 14 d | 4 g oral ld → 1.2 g tid or 8 mg/kg iv tid × 14 d | Lop/r 400/100mg bid orally ´ 14 d. Tailing steroid regimen × 21 d and pulsed Mp | 21-d adverse outcome (ARDS or death) was 28.8% for the historical control vs 2.4% in the initial treatment group (P < 0.001). No deaths in the treatment group | Mild gastrointestinal adverse-effects. Anemia (70%) → 2 pts transfused. 26.8% bradycardia | Apparent favorable clinical response to combination of Lop/r + RBV + steroids when needed | The second study showing statistically significant benefits from the combination of RBV+ Lop/r + ster when early applied in the disease course |
| Cheng et al[142], Hong Kong6 | 772 | No data available | No data available | Steroids Lop/r | No data available | No | 675 pts received RBV and 44 Lop/r. No obvious difference noted irrespective of treatment combination | In Table 2 of the article however, RBV + Lop/r + ster provided a CFR of 2.3%, IFN + ster 0%, RBV + pulsed Mp 5.9% and RBV + ster 7.7% compared to a 15.4% of supportive treatment |
| Lau et al[143], Hong Kong, Canada7 | Integrated data base containing 1755 HK pts and 191 Toronto cases | Within 2 d from hospital admission | No data available | Data showed for HK pts crude CMR 23.3% in neither treatment, 29.4% in steroids, 8.9% in RBV and 12.6% for combination. For Toronto pts no treatment 20%, RBV 9.3% and RBV + ster 12.8%. Authors adjusted these results for propensity scores and balance was achieved among all pts characteristics. Side-effects not considered in this study | Estimated CFRs based on the generalized propensity score weighting, the model predicted that the overall CFR would have been highest if all pts in HK had been treated with RBV + steroids, whereas it would have been the lowest if none treated. Toronto results were consistent. The combination of RBV + ster has no therapeutic benefit | The generalized propensity score weighting model prediction reversed the initial finding for CFR 12.7% of the combination to 19.2% and of untreated from 23.3% to 15.4% (!!). Inconclusive study (Pitfall 5) | ||
| MERS clinical studies | ||||||||
| Omrani et al[161], Saudi Arabia2 | 44 with severe pneumonia 20 treated 24 control. Scores APACHE II: 27, and SOFA: 11 | 3 d from diagnosis | 2 g ld → 1.2 g tid 4 d → 600 mg tid × 4-6 d. Dosing adjusted to Crcl. Orally RBV | Antibiotics, Oseltamivir, PegIFN-α2α sc 180 μg/wk for 2 wk. Hc 200 mg/d in pts with refractory septic shock | 41/44 intubated. 14-d mortality: treat 6/20 vs control 17/24 (P = 0.004). 28-d: treat: 14/20 vs control 20/24 (P = 0.054) | RBV well tolerated. Hb drop in treat > control (P = 0.002). No differences in transfusions, no treatment discontinuation | Significant benefit in 14-d survival. The loss of difference in 28-d might be explained by high initial APACHE II and SOFA scores and several comorbidities | Surprisingly, statistically significant results despite that eligible patients had initially severe pneumonia (Phase 2) (Pitfall 4) without high dose steroids applied. Long- lasting IFNs (peg) might not be the best form for acute infections |
| Shalhoub et al[162], Saudi, Arabia2 | 32 pts were already under MERS pneumonia and some with respiratory failure | For IFNs: 1 d after MERS diagnosis. For RBV not reported | 2 g ld orally → 600 mg bid | Antibiotics, IFN-α2a sc 180 μg/wk × 2 wk. IFN-β1a sc44 μg × 3 times/wk | Overall mortality: 22/32 (69%). IFN-α2a + RBV: 11/13 (85%). IFN-β1a + RBV: 7/11 (64%). Hemodialysis pts: 14/14 (100%) | No | IFN-α2a or IFN-β1a + RBV were ineffective against MERS mortality | Unknown time-gap between symptom onset and treatment initiation. Very low RBV dose applied (Pitfall 3). In specific cases with severe pneumonitis high-dose steroids and Mp pulses should have been used for better outcomes (Pitfall 4) |
| Al Ghamdi et al[171], Saudi, Arabia2 | 51 pts | No data reported | No data reported | Antibiotics, IFN-α, IFN-β, MMF, Hc in 5 pts | 31 pts received antivirals (IFNs,RBV) in several combinations, 8 pts MMF all survived. (IFN-β and MMF were given to less severely pts). CMR = 37% | No | IFN-β and MMF were predictors of increased survival | No time gap from symptom onset reported. No dosing reported. Inconclusive study for RBV treatment |
| Choi et al[172], Korea8 | 186 pts | 6 d (1-20 d) 14% of pts within 48 h | 81% IFN-α + RBV + Lop/r, 12.7% IFN-α + RBV, 5.0% RBV + Lop/r, No dosing regimens reported | CMR = 20.4% lower than others ranging 36.5%-65% | No | Unable to assess the clinical impact of therapies as most pts received antivirals | No dosing regimens, not duration reported | |
| Arabi et al[166], Saudi, Arabia9 | 309/151 pts critically ill received steroids | 3 d from ICU admission | Antivirals: RBV, IFN, RBV + IFN, oseltamivir. The median of the maximum daily Hc-equivalent was 300 mg with a median duration of 7 d | CMR 74.2% vs 57.6% (no steroids). After adjustment for baseline and time-varying confounders the use of steroids was not associated with increased 90-d mortality but with delayed RNA clearance | No | Steroids were commonly used in critically ill patients with MERS. Pts given steroids were more likely to have 1 or more comorbidities than those who did not (P = 0.001) | No Mp pulses were administered. Maximum Hc doses reported (300 mg) are equivalent to only 60 mg of Mp. In addition, authors do not comment about the impact of the co- administered antivirals (Pitfall 5) | |
| Habib et al[163], Saudi Arabia2 | 63/61pts presented with severe illness (pneumonia 87.3% and septicemia 11%) | No data reported | No data reported | No data reported | Overall CMR 25.4%. Treated 22.9%. Survivors were more likely to have had received IFN + RBV than those who died (P = 0.01) | No | CMR 25% comparable to that of Omrani 30%, lower than AlMekhlafi (74.2%), Khalid (55%), and Al-Tawgiq (100%). Unable to determine the combination efficacy in the absence of a reference group | No dosing regimen, no time-gap from onset. The severity in admission probably implies an advanced disease phase, where antivirals are less effective (Pitfall 4) |
| Arabi et al[166], Saudi, Arabia2 | 349/144 critically ill all ICU pts | 2d from ICU admission but 9 d (6-12) from symptom onset | RBV: 2 g ld po → 1.2 g po tid × 4 d → 600 mg tid po × 4-6 d | Peg-IFN-α2b → 1.5 mcg/kg sc × 2 wk Per-IFN-α2a → 180 μg/wk × 2 wk Peg-IFN-β1a → 44 mg sc × 3/wk | Crude CMR was higher in antiviral treated group 73.6% vs 61.5% (P = 0.02). However, with a marginal structural model there was no significant difference in 90-d mortality (aOR: 1.03; 95%CI: 0.73-1.44, P = 0.87). Also, no significant difference in RNA clearance (aOR: 0.65; 95%CI: 0.3-1.44, P = 0.29) | During ICU stay RBV/IFN treated pts were more likely to receive steroids (59.7% vs 44.9%P = 0.006). Future studies should test the efficacy of newer antiviral interventions | Very late antiviral initiation. Possible higher needs for steroids in antiviral – treated group could imply more severely ill pts (Pitfalls 2, 5) | |
| AlMekhlafi et al[167], Saudi, Arabia2 | 31 pts in ICU. 13 pts received RBV+ IFN-α2α | ICU pts | Not reported | Not reported | CMR 74.2%. Among 13 pts who were given antivirals, 9 died | No | All pts who received either oseltamivir or RBV + IFN-α2a had no favorable outcomes | Antivirals may have no efficacy in Phase II-III of MERS (Pitfall 4) |
| Khalid et al[168], Saudi, Arabia2 | 14 pts intubated 11 pts received RBV | 6 d | Not reported | Antibiotics RBV + Peg-IFN-α2a, Mp 1 mg/kg/d × 7 d | 9 pts died in the ICU, 5 discharged | No | MERS with ARDS has high mortality rates. The role of RBV + IFN warrants further evaluation | Antivirals may have no effect in Phase II-III of MERS-infected pts under mechanical ventilation (Pitfall 4) |
| Khalid et al[164], Saudi, Arabia2 | 6 pts, 3 cases 74-84 yr, 3 cases 17-54 yr | 1st group 12-19 d; 2nd group 1-2 d | 2 g ld → 1.2 g tid × 4 d → 0.6 g tid × 4-6 d | IFN-α2b sc 180 μg/wk × 2 wk. 1 case received pulsed Mp and recovered | 1st group pts all died. 2nd group all recovered | No | Combination of RBV and IFN-α2b have a role in treatment of MERS if started early in disease course | Very late (12-19 d) antiviral initiation in 1st group when disease is already in the ARDS phase (Pitfall 4). 1 case was helped by Mp pulses |
| Al-Tawfiq et al[169], Saudi, Arabia | 5/5 | 11-21 d (after admission) | 2 g ld → 400 mg po tid | Antibiotics Oseltamivir IFN-α2b Mp 40 mg tid or Ps 40 mg/d | All died | No | All pts were already intubated when treatment started | Antivirals in Phase 2, very low RBV dosing, low ster dosing for Phase 2-3 (Pitfalls 2, 3, 4) |
| Park et al[159], Korea2 | 43 HCW with high-risk exposure to MERS pneumonia pts. 21 HCW with more severe exposure received PEP. 22 HCW no PEP | Within 36 h after unprotected exposure | RBV 2.0 g ld orally → 1.2 g tid × 4 d → 600 mg tid × 6-8 d | Lop/r 400/100 mg bid × 11-13 d | 6/43 HCW exposed developed MERS infection. The attack rate was lower in the PEP vs no-PEP (0% vs 28.6% OR: 0.405 P = 0.009). No MERS infection in PEP group. Only PEP therapy reduced significantly the risk of MERS infection (OR: 0.714; P = 0.009) | Mild: diarrhea, nausea, anemia, stomatitis, leucopenia, hyperbilirubinemia. No PEP discontinuation. All normalized after completion of PEP | PEP therapy was associated with a 40% decrease in the risk of infection | The only study reporting results of PEP prophylaxis with the combination of Lop/r + RBV. Ok |
| COVID-19 clinical studies | ||||||||
| Tong et al[189], China2 | 115/44 pts Severe disease. 9 pts intubated 28 pts NINV | 8 d from onset 4 d from diagnosis | 500 mg iv bid | Antibiotics | Negative conversion time of SARS-CoV-2 test in RBV vs control (12.8 d vs 14.1 d, P = 0.314) CFR 17.1% vs 24.6% (P = 0.475) | No side effects. No difference in anemia | RBV administration was doctor-dependent and sometimes RBV was out of stock. In severe COVID-19 RBV is not associated with improved negative conversion time for SARS-CoV-2 test or improved mortality | Pitfall 2. Relatively moderate RBV dosing (Pitfall 3). Possibly not regular RBV administration (Pitfall 5) |
| Li et al[190], China2 | 151 pts, Number of pts treated with RBV was not specified. Moderate to critical disease | Not reported | 500 mg iv bid or tid × 10 d | Umifenovir Lop/r, Traditional medicine, Peramivir, Oseltamivir, Penciclovir Ganciclovir | 25 pts discharged 25 pts hospitalized 79 pts clinical improvement7 died (CFR = 4.6%) | The use of two-step clustering and subgroup analysis enabled an in-depth analysis of the effects of single or combined antiviral therapy. Following the antiviral therapy, there was indeed an improvement of severe patients' condition. Combination was superior to single or dual agents. A quadruple combinationof Umifenovir + RBV + Lop/r+ Lianhua Qingwen has been recommended for critically ill COVID-19 pts | Incomplete data (time-gap from symptom onset to treatment initiation) (Pitfall 5) | |
| Yuan et al[191], China2 | 94 pts, 46 pts IFN-α + Lop/r.21 pts IFN-α + Lop/r + RBV. Median age 40 yr. 15 pts, 1 or 2 comorbiditie. Mild disease: 8 pts. Moderate: 75 pts. Critical: 11 pts | Hospitalized 7d after symptom onset | No data reported | No data reported | Significant correlation between the length of hospital stay and PCR negative conversion time in pts treated with IFN + Lop/r (P = 0.012) and with IFN + Lop/r + RBV (P = 0.0215). No death, no intubation, all recovered | No | These two regimens might be beneficial for COVID-19 treatment | Pitfall 2. No dosing regimens reported. Ok |
| Wu et al[192], China9 | 80/80 pts, 41 females, 46.1 yr. 77 pts mild to moderate symptoms. 3 pts severe. 38 pts chronic diseases | Not reported | Not reported. Duration 7 d | Moxifloxacin duration 7 d12 pts Mp to alleviate the shortness of breath | No death, no INV. 35 pts NINV. 55 pts abnormal chest CT. 3 pts transaminitis. 1 pt hemodialysis. As of writing, 21 pts discharged (stay 8 d) | No | Notably, infected patients may be falsely excluded based on 2 consecutively negative respiratory pathogenic PCR tests | Surprisingly, authors do not discuss at all the role of treatment administered (RBV + Mp + Moxi) (Pitfall 5) |
| Chen et al[193], China2 | 681 pts with severe disease/279 received RBV. 375 pts had comorbidities. Median 65 yr. 40-65 yr 46.1% of pts, > 65 yr 47.1% of pts | No time-gap between symptom onset and initiation of treatment, no dosing regimens reported, or drug combinations. 666 pts received antivirals, antibiotics (83.8%), IVIG (54.6%), and steroids (48.8%) | In a report from China overall mortality from COVID-19 was 2.3% while in critical cases 49%. In another from Italy CFR was 26% in ICU pts. Another study indicated a mortality of 15% while in ICU cases 38%. In this study CFR was 15.3%. 45.8% of the pts had preexisting cardiovascular disease, of which 23.4% died. In multivariate analysis, RBV and arbidol were positively associated with death, OR: 0.208 (95%CI: 0.07-0.618; P = 0.005). Of notice, RBV might have a beneficial effect in severe COVID-19 pts with cardiovascular diseases and cardiac injury by disease. Therefore, every drug regimen should include arbidol or RBV for severe cases | Impressive findings for both antivirals in reducing mortality in severe cases. The beneficial effect of RBV in cardiac injury is supported by another study which showed that RBV is mostly concentrated in heart and intestines | ||||
| Peng et al[197], China2 | 75 pediatric pts. 8 most critical cases received RBV + IFN-α | 4.9 d | 10 mg/kg/d bid iv | IFN-α neb1-4 μg/kg/d bid. Antibiotics, arbidol 5 pts, oseltamivir 20 pts | All discharged. Length of hospital stay 10.6 d and SARS-CoV-2 clearance 6.4 d. The two most severe cases were treated with RBV | No | Severity in pediatric pts milder than adults. The efficacy of antiviral therapy in children remains to be evaluated | Ok |
| Huang et al[201], China10 | 101 pts, 33 pts RBV + IFN-α, 36 pts IFN-α + Lop/r, 32 pts RBV + Lop/r + IFN-α, Mild to moderate severity | 4 d to enrollment | 2.0 g ld iv → 400-600 mg tid depending on bw × 14 d | Lop/r 400/100 mg bid × 14 d IFN-α in h 5 MU bid × 14 d | SARS-CoV-2 time to negativity 12 d in group 2 vs 13 and 15 d in groups 1 and 3 (P = 0.23). Higher proportion of nucleic acid negativity in group 2 (61.1%) than (51.5% and 46.9%) in groups 1 and 3 in 14 d | GI side-effects mainly in the triple combination | No significant differences among the three regimens in terms of antiviral efficacy. Significant GI effects in the triple combination | Ok |
| Hung et al[202], China11, Open-label Phase 2 trial | 127/81 pts 81 RBV + Lop/r + IFN-β1b. 41 Lop/r (control). Median age 52 yr. Men 54%, 51 pts had underlying diseases. Mild to moderate COVID-19 | Triple combination: 5 d, control: 4 d | 400 mg bid × 14 d | Oral Lop/r 400/100 mg IFN-β1b 8MU on alternate day sc up to 3 doses (within 1st wk). Hc 50 mg tid in oxygen desaturation | Abnormal chest X-ray in 96 pts. 17 pts oxygen desaturation → 6 in ICU, 1 intubated (96 yr) but extubated after 10 d. No one succumbed. Time to negative swab from treatment initiation in combo 7 d vs 12 d in control (P = 0.001) | Mild and self-limiting. Diarrhea, nausea, transaminitis, all resolved within 3 d from treatment initiation | Time to NEWS2 0 in combo 4 d vs 8 d (P = 0.0001) in control and time to SOFA 0 in combo 3 d vs 8 d in control (P = 0.041). Hospital stay duration: combo 9 d vs 14.5 d in control (P = 0.016). In subgroup analysis when authors compared pts with early (< 7 d) treatment initiation in both groups, all comparisons where statistically very significant (P < 0.0001) including improvement in NEWS2 and SOFA scores, and time to negative viral loads | Early antiviral triple therapy is superior to lop/r in shortening shedding, alleviating symptoms and facilitating discharge of pts with mild to moderate COVID 19. Ok |
| Eslami et al[199], Iran12 | 62/27pts All treated with SOC: Lop/r + HCQ | Not reported (at admission) | RBV 600 mg bid × 14 d | Sof/ daclatasvir 400/60 mg qd. All treated with Lop/r 400/100 mg bid × 5 d and HCQ 400 mg single dose | Median stay 5 d for Sof/d vs 9 d for RBV. CFR 6% in Sof/d vs 33% in RBV. Relative risk of death for those treated with Sof/d0.17 (95%CI: 0.04-0.73; P = 0.02) | Mild adverse effects reported but no discontinuation was demanded | Given these encouraging initial results, further investigation in larger-scale trials seems warranted | Unclear time-gap from disease onset to RBV initiation. Low RBV dosing. Confusing study as both arms were concurrently treated with other anti-coronaviruses agents (Pitfalls 3, 5) |
| Kasgari et al[200], Iran13 | 48 pts moderate disease, 24 pts → Sof/d + RBV24 pts → SOC: Lop/r + HCQ + RBV depending on recommendations at the time of the study | Not reported | RBV 600 mg bid | The median duration of hospital stay, number of ICU admissions, and number of deaths: no statistically significant differences between the two groups. Only trends for recovery and lower deaths in the Sof/d + RBV arm | Very small number of participants, Pt 2 unclear, fell under Pt3. Confounding results as both arms were concurrently being treated with antivirals, even with RBV (Pitfalls 2, 3, 5) | |||
| Liu et al[198], China14 | Enrolled studies with COVID-19 (n = 12), MERS (n = 2), SARS (n = 4) and influenza (n = 1) | Interventions in the studies RBV (n = 3), HCQ (n = 5), favipinavir (n = 3), IFN (n = 3), Lop/r (n = 2), umifenovir (n = 1) | This review did not find persuasive evidence of benefit for treatment using RBV in a population of pts with COVID-19 and results from studies evaluating SARS or MERS provided no support for a reduction in mortality with RBV treatment[85,119,171] | Only treatment with Lop/r for which authors found low-quality evidence for a decrease in hospital stay in ICU. To date, persuasive evidence of important benefit in COVID-19 does not exist for any antiviral although for each treatment evidence has not excluded important benefit | Very controversial conclusion (Pitfall 5) | |||
| Zhong et al[88], China14 | COVID-19 = 7 studies. SARS = 9, MERS = 2, RBV = 4 studies, RBV + Lop/r + ster = 2, RBV + IFNs = 3, RBV + ster = 1 | Compared with comparators, interventions notably reduce mortality (RR: 0.65, 95%CI: 0.44-0.96, I2 = 81.3%). In subgroup analysis, the combination of RBV + ster remarkably decreased mortality (RR: 0.43, 95%CI: 0.27-0.68). Besides, Lop/r, RBV, RBV + IFN and combination of Lop/r + RBV + ster showed tendency of lower mortality. Interventions also remarkably ameliorated clinical and radiological improvement, without manifesting clear effect on virological eradication (except for Lop/r-based regimens), incidence of ARDS, intubation, and adverse effects | In conclusion, there was evidence of lower mortality, better clinical and radiological improvement in intervention group compared to control | A very large meta-analysis with remarkable conclusions for coronaviruses treatment. Ok | ||||
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 | |
- Citation: Liatsos GD. Controversies’ clarification regarding ribavirin efficacy in measles and coronaviruses: Comprehensive therapeutic approach strictly tailored to COVID-19 disease stages. World J Clin Cases 2021; 9(19): 5135-5178
- URL: https://www.wjgnet.com/2307-8960/full/v9/i19/5135.htm
- DOI: https://dx.doi.org/10.12998/wjcc.v9.i19.5135