PMC:7652766 / 86806-99376 JSONTXT

{"project":"LitCovid-PD-HP","denotations":[{"id":"T127","span":{"begin":965,"end":981},"obj":"Phenotype"},{"id":"T128","span":{"begin":3742,"end":3747},"obj":"Phenotype"},{"id":"T129","span":{"begin":3768,"end":3777},"obj":"Phenotype"},{"id":"T130","span":{"begin":4255,"end":4260},"obj":"Phenotype"},{"id":"T131","span":{"begin":6540,"end":6549},"obj":"Phenotype"},{"id":"T132","span":{"begin":6974,"end":6983},"obj":"Phenotype"},{"id":"T133","span":{"begin":11240,"end":11249},"obj":"Phenotype"}],"attributes":[{"id":"A127","pred":"hp_id","subj":"T127","obj":"http://purl.obolibrary.org/obo/HP_0002721"},{"id":"A128","pred":"hp_id","subj":"T128","obj":"http://purl.obolibrary.org/obo/HP_0001945"},{"id":"A129","pred":"hp_id","subj":"T129","obj":"http://purl.obolibrary.org/obo/HP_0031246"},{"id":"A130","pred":"hp_id","subj":"T130","obj":"http://purl.obolibrary.org/obo/HP_0001945"},{"id":"A131","pred":"hp_id","subj":"T131","obj":"http://purl.obolibrary.org/obo/HP_0002090"},{"id":"A132","pred":"hp_id","subj":"T132","obj":"http://purl.obolibrary.org/obo/HP_0002090"},{"id":"A133","pred":"hp_id","subj":"T133","obj":"http://purl.obolibrary.org/obo/HP_0002090"}],"text":"Antivirals\nDue to the large amount of experimental and clinical studies assessing the effectiveness of antiviral therapy against SARS-CoV-2, we have seen the importance of this class of drugs in reducing the viral load peak at the beginning of the infection. Evidence from laboratory, animal, and clinical studies demonstrate that the use of associated or isolated antivirals can delay the progression of lung lesions and decrease the possibility of respiratory transmission of SARS-CoV-2. In this study, we selected the following most promising treatment options: lopinavir/ritonavir, arbidol, ribavirin, remdesivir, favipiravir, and type I IFN.\nIn the context of discovering new drugs, it is efficient to test the efficacy of existing antiviral drugs regarding the treatment of related viral infections. After the emergence of SARS in 2003, the screening of approved drugs identified an effective SARS-CoV-2 antiviral-drug candidate: the combination of the human immunodeficiency virus (HIV) protease inhibitors lopinavir and ritonavir. However, lopinavir has insufficient oral bioavailability for significant therapeutic activity due to rapid catabolism by the cytochrome P450 enzyme system. Thus, ritonavir is a cytochrome P450 and glycoproteins inhibitor, which increases the lopinavir plasma half-life, enhancing the pharmacokinetic and pharmacodynamic activities against the viral HIV-protease (303).\nChu et al. (304) described the possible mechanism of action of these drugs on SARS-CoV-1, suggesting that they act by inhibiting intracellular viral multiplication, preventing the action of the protease enzyme, which leads to the formation of an immature and less infectious virus with no ability to replicate.\nChoy et al. (305) were successful at demonstrating the antiviral effect of lopinavir against SARS-CoV-2, but this was not the case for ritonavir. In turn, Kang et al. (306) found a lower viral load in infected SARS-CoV-2 Vero cells treated with lopinavir/ritonavir in relation to the untreated infected control. Although no consensus has been reached on its efficacy, dosage, or administration period, the literature includes some case reports, case series, and observational studies reporting a protective effect of the lopinavir/ritonavir combination in COVID-19 patients (110, 307–312).\nConversely, Cao et al. (313) conducted a controlled open‐label study with 199 hospitalized severe COVID‐19 patients randomly divided into two groups: a standard care group and a lopinavir/ritonavir treatment group (400 mg/100 mg). No benefit was observed in the lopinavir/ritonavir treatment group, showing no significant results for faster clinical improvement, lower mortality, or decreased viral RNA detectability. Although there are 85 clinical trials in progress testing lopinavir/ritonavir associated with other drugs on SARS-CoV-2 and/or COVID-19, WHO stopped the study of lopinavir/ritonavir in the Solidarity Trial.\nDeng et al. (312) have studied the association of lopinavir/ritonavir with arbidol treatment and demonstrated a significant improvement in COVID-19 patients compared with a group treated only with lopinavir/ritonavir. Arbidol (umifenovir) is a broad-spectrum antiviral and immunomodulatory compound used to treat influenza and many other viruses (314). Analyses of molecular dynamics and structure-guided drug-binding have suggested an efficiency of arbidol at blocking or hampering the trimerization of the SARS-CoV-2 spike glycoprotein, in addition to inhibiting virus-cell interactions, which supports the potential use of arbidol to treat COVID-19 (315).\nChen et al. (316) demonstrated that arbidol therapy was able to shorten the course of the disease and promote clinical improvement, resulting in low fever and improvements in dry cough without side effects faster than the control group. Zhu et al. (317) also demonstrated the effects of arbidol by retrospectively analyzing the clinical data from 50 COVID-19 patients. The study demonstrated that the use of arbidol monotherapy, without association with other drugs, was more effective than the treatment with lopinavir/ritonavir, showing clinical improvement of the disease, presenting a total elimination of viral load over a shorter duration; in addition, no fever or ARDS were reported compared with those in the lopinavir/ritonavir group.\nRibavirin is another antiviral drug used in association with lopinavir/ritonavir to treat SARS-CoV-1 and was able to reduce viral load, risk of adverse clinical outcomes, ARDS, or death in SARS patients (304, 318). Ribavirin has a broad antiviral spectrum as it is a nucleotide analog that competes for the active site of RdRp, a crucial enzyme in the life cycle of RNA viruses, inhibiting viral replication and transcription (221, 319, 320).\nElfiky (320) conducted an in silico study demonstrating that ribavirin and other antivirals such as sofosbuvir can strongly bind to coronavirus RdRp, preventing the transcription of new copies of viral RNA. Only a few clinical studies have investigated the effect of ribavirin on COVID-19 patients, with the studies available generally focusing on the association of ribavirin and other therapeutic schemes (321–323). Nevertheless, China’s government (324) has recommended the use of ribavirin in COVID-19 patients.\nRemdesivir (RDV) is also among the several potential drugs tested for SARS-CoV-2 treatment. Originally developed to treat Ebola virus infection, RDV is active against RNA viruses from different families, including Coronaviridae (e.g., SARS-CoV-1 and MERS-CoV) (325). RDV showed an in vitro effective antiviral activity against SARS-CoV-2 (326). Grein et al. (327) conducted a cohort study with 53 COVID-19 patients treated with RDV and found that 68% of them had improved oxygen-support class, whereas 57% of the patients receiving mechanical ventilation were extubated. Overall mortality reached 13% over a median follow-up of 18 days, however, viral load data were not collected to confirm the antiviral effects of RDV. The biggest issue with this study is that the authors did not include a group without RDV, which hampers the performance of comparative statistical analyses to prove whether the data found resulted from the treatment with RDV.\nAnother double-blind, randomized, placebo-controlled trial of intravenous RDV conducted in adults hospitalized with COVID-19 with evidence of lower respiratory tract involvement was performed in different parts of the world (328). The study of Beigel and colleagues (328) enrolled 1,063 COVID19 pneumonia patients, 538 of whom were assigned to the treatment with RDV and 521 to a placebo, showed the effectiveness of RDV in treating COVID-19 patients. The drug was superior to the placebo in reducing the recovery time in hospitalized COVID-19 patients and decreased the mortality rate in the RDV group, however, this result did not reach statistical significance.\nAntionori et al. (329), analyzing patients with severe COVID-19 pneumonia in an intensive care unit (ICU) who were treated for 10 days with RDV, found that on the 28th day, 38.9% showed improvement, 16.7% were still on mechanical ventilation, and 44.4% died. The data suggest that this treatment can benefit hospitalized patients who are not in the ICU, where the clinical result was better and adverse events are observed less frequently.\nAlternatively, the randomized, double-blind, placebo-controlled, multicenter trial with 273 ill individuals performed by Wang et al. revealed that RDV intravenous administration was well-tolerated in COVID-19 patients. However, the authors did not find any clinical improvement or significant antiviral effect. Goldman et al. (330), in another phase 3 clinical trial on 397 patients with severe COVID-19 without mechanical ventilation support, also did not find differences between 5-day and 10-day courses of RDV therapy. The RDV data currently available are still controversial, however, dozens of clinical studies are currently using this drug as an alternative treatment for COVID-19, possibly further elucidating its effects.\nThe efficiency of favipiravir, another anti-influenza RdRp inhibitor, has also been clinically assessed and was approved for COVID-19 treatment in China, March 2020 (331, 332). An experimental study carried out with the VERO cell line showed that the drug has in vitro activity against SARS-CoV-2 (326). Aiming at comparing the effects of favipiravir and lopinavir/ritonavir, Cai et al. (333) conducted an open, non-randomized, before-after controlled study with 80 patients and found that favipiravir favored viral clearance and improved chest CT, having caused fewer adverse effects than the lopinavir/ritonavir group. Currently, 31 clinical trials using this medication are in progress.\nRegarding antivirals, type I IFN is a group of cytokines comprising the α and β subtypes, among others, with an important role in antiviral immunity that interferes with viral replication, as discussed above. Many studies have shown the protective effect of type I IFN associated with antiviral therapies for patients with SARS and MERS [reviewed by Sallard et al. (334)], which arouses the interest of the scientific community in type I IFN as a potential treatment against SARS-CoV-2 (334–337). Despite their efficacy against SARS-CoV-2 (338, 339), the results of in vitro studies using IFN-α and -β to treat COVID-19 patients remain inconclusive.\nSuch uncertain nature of the results is associated with biases present in these studies, which include limited-size sample, heterogeneous experimental designs/clinical status, and the type of IFN isoform tested. In addition, since COVID-19 treatments rarely involve monotherapy, it is difficult to assess whether the results derived from the tested IFN or the drugs used in combination (322, 323, 340–343). It is also worth mentioning that, as discussed above, type I IFN appears to exacerbate inflammation in the progression to severe COVID-19; the timing of administration and subgroups targeted for treatment with type I IFN need to be considered with caution.\nA recent retrospective multicenter cohort study of 446 Chinese patients with COVID-19 reported that among severe to critical COVID-19 patients, early administration (≤5 days after admission) of IFN-α2b decreased mortality in comparison with no admission of IFN-α2b, whereas no significant benefit was associated with IFN-α2b use in moderately ill patients. However, late use of IFN-α2b increased mortality and delayed recovery of severe to critical COVID-19 patients (344).\nZhou et al. (341), investigated the isolated effect of IFN-α in a cohort study comparing 77 patients with moderate COVID-19 treated with nebulized IFN-α2b (5 mU b.i.d.), oral arbidol (200 mg t.i.d.), or a combination of both. Although the study did not include a control group, the treatment with IFN-α2b, either containing arbidol or not, significantly reduced the duration of detectable virus in the upper respiratory tract and the circulating of inflammatory markers (IL-6 and C-reactive protein levels).\nStill, in a retrospective multicenter cohort study with 141 mild COVID-19 patients by Xu et al. (342), the arbidol/IFN-α2b combination proved more effective in accelerating pneumonia recovery than IFN-α2b monotherapy, but this was not the case for viral clearance or reducing the length of hospital stay than IFN-α2b monotherapy.\nHung et al. (322) assessed the effect of IFN-β on COVID-19 patients and found that the triple combination of IFN-β1b, lopinavir/ritonavir, and ribavirin was safer and more effective than lopinavir/ritonavir alone at alleviating symptoms, shortening the duration of viral shedding and hospital stay in patients with mild to moderate COVID-19. Similarly, an open randomized clinical trial was carried out by Danoudi-Monfared et al. (345), analyzing treatment with IFN-β-1a. The IFN group of COVID-19 patients (n=42) received IFN β-1a in addition to the protocol medications (hydroxychloroquine plus lopinavir-ritonavir or atazanavir-ritonavir) while the control group (n=39) received only the protocol medications. The IFN-β-1a-treated patients showed a significantly increased discharge rate on day 14 and decreased mortality within 28 days. A better survival rate was also observed when patients received IFN- β-1a in the early stage of the disease.\nThe COVID-19 treatment guidelines of many countries already recommend the use of IFNs α/β (335). Currently, all over the world, more than 20 clinical trials are using IFN-α and/or β alone or in association with other drugs."}

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Evidence from laboratory, animal, and clinical studies demonstrate that the use of associated or isolated antivirals can delay the progression of lung lesions and decrease the possibility of respiratory transmission of SARS-CoV-2. In this study, we selected the following most promising treatment options: lopinavir/ritonavir, arbidol, ribavirin, remdesivir, favipiravir, and type I IFN.\nIn the context of discovering new drugs, it is efficient to test the efficacy of existing antiviral drugs regarding the treatment of related viral infections. After the emergence of SARS in 2003, the screening of approved drugs identified an effective SARS-CoV-2 antiviral-drug candidate: the combination of the human immunodeficiency virus (HIV) protease inhibitors lopinavir and ritonavir. However, lopinavir has insufficient oral bioavailability for significant therapeutic activity due to rapid catabolism by the cytochrome P450 enzyme system. Thus, ritonavir is a cytochrome P450 and glycoproteins inhibitor, which increases the lopinavir plasma half-life, enhancing the pharmacokinetic and pharmacodynamic activities against the viral HIV-protease (303).\nChu et al. (304) described the possible mechanism of action of these drugs on SARS-CoV-1, suggesting that they act by inhibiting intracellular viral multiplication, preventing the action of the protease enzyme, which leads to the formation of an immature and less infectious virus with no ability to replicate.\nChoy et al. (305) were successful at demonstrating the antiviral effect of lopinavir against SARS-CoV-2, but this was not the case for ritonavir. In turn, Kang et al. (306) found a lower viral load in infected SARS-CoV-2 Vero cells treated with lopinavir/ritonavir in relation to the untreated infected control. Although no consensus has been reached on its efficacy, dosage, or administration period, the literature includes some case reports, case series, and observational studies reporting a protective effect of the lopinavir/ritonavir combination in COVID-19 patients (110, 307–312).\nConversely, Cao et al. (313) conducted a controlled open‐label study with 199 hospitalized severe COVID‐19 patients randomly divided into two groups: a standard care group and a lopinavir/ritonavir treatment group (400 mg/100 mg). No benefit was observed in the lopinavir/ritonavir treatment group, showing no significant results for faster clinical improvement, lower mortality, or decreased viral RNA detectability. Although there are 85 clinical trials in progress testing lopinavir/ritonavir associated with other drugs on SARS-CoV-2 and/or COVID-19, WHO stopped the study of lopinavir/ritonavir in the Solidarity Trial.\nDeng et al. (312) have studied the association of lopinavir/ritonavir with arbidol treatment and demonstrated a significant improvement in COVID-19 patients compared with a group treated only with lopinavir/ritonavir. Arbidol (umifenovir) is a broad-spectrum antiviral and immunomodulatory compound used to treat influenza and many other viruses (314). Analyses of molecular dynamics and structure-guided drug-binding have suggested an efficiency of arbidol at blocking or hampering the trimerization of the SARS-CoV-2 spike glycoprotein, in addition to inhibiting virus-cell interactions, which supports the potential use of arbidol to treat COVID-19 (315).\nChen et al. (316) demonstrated that arbidol therapy was able to shorten the course of the disease and promote clinical improvement, resulting in low fever and improvements in dry cough without side effects faster than the control group. Zhu et al. (317) also demonstrated the effects of arbidol by retrospectively analyzing the clinical data from 50 COVID-19 patients. The study demonstrated that the use of arbidol monotherapy, without association with other drugs, was more effective than the treatment with lopinavir/ritonavir, showing clinical improvement of the disease, presenting a total elimination of viral load over a shorter duration; in addition, no fever or ARDS were reported compared with those in the lopinavir/ritonavir group.\nRibavirin is another antiviral drug used in association with lopinavir/ritonavir to treat SARS-CoV-1 and was able to reduce viral load, risk of adverse clinical outcomes, ARDS, or death in SARS patients (304, 318). Ribavirin has a broad antiviral spectrum as it is a nucleotide analog that competes for the active site of RdRp, a crucial enzyme in the life cycle of RNA viruses, inhibiting viral replication and transcription (221, 319, 320).\nElfiky (320) conducted an in silico study demonstrating that ribavirin and other antivirals such as sofosbuvir can strongly bind to coronavirus RdRp, preventing the transcription of new copies of viral RNA. Only a few clinical studies have investigated the effect of ribavirin on COVID-19 patients, with the studies available generally focusing on the association of ribavirin and other therapeutic schemes (321–323). Nevertheless, China’s government (324) has recommended the use of ribavirin in COVID-19 patients.\nRemdesivir (RDV) is also among the several potential drugs tested for SARS-CoV-2 treatment. Originally developed to treat Ebola virus infection, RDV is active against RNA viruses from different families, including Coronaviridae (e.g., SARS-CoV-1 and MERS-CoV) (325). RDV showed an in vitro effective antiviral activity against SARS-CoV-2 (326). Grein et al. (327) conducted a cohort study with 53 COVID-19 patients treated with RDV and found that 68% of them had improved oxygen-support class, whereas 57% of the patients receiving mechanical ventilation were extubated. Overall mortality reached 13% over a median follow-up of 18 days, however, viral load data were not collected to confirm the antiviral effects of RDV. The biggest issue with this study is that the authors did not include a group without RDV, which hampers the performance of comparative statistical analyses to prove whether the data found resulted from the treatment with RDV.\nAnother double-blind, randomized, placebo-controlled trial of intravenous RDV conducted in adults hospitalized with COVID-19 with evidence of lower respiratory tract involvement was performed in different parts of the world (328). The study of Beigel and colleagues (328) enrolled 1,063 COVID19 pneumonia patients, 538 of whom were assigned to the treatment with RDV and 521 to a placebo, showed the effectiveness of RDV in treating COVID-19 patients. The drug was superior to the placebo in reducing the recovery time in hospitalized COVID-19 patients and decreased the mortality rate in the RDV group, however, this result did not reach statistical significance.\nAntionori et al. (329), analyzing patients with severe COVID-19 pneumonia in an intensive care unit (ICU) who were treated for 10 days with RDV, found that on the 28th day, 38.9% showed improvement, 16.7% were still on mechanical ventilation, and 44.4% died. The data suggest that this treatment can benefit hospitalized patients who are not in the ICU, where the clinical result was better and adverse events are observed less frequently.\nAlternatively, the randomized, double-blind, placebo-controlled, multicenter trial with 273 ill individuals performed by Wang et al. revealed that RDV intravenous administration was well-tolerated in COVID-19 patients. However, the authors did not find any clinical improvement or significant antiviral effect. Goldman et al. (330), in another phase 3 clinical trial on 397 patients with severe COVID-19 without mechanical ventilation support, also did not find differences between 5-day and 10-day courses of RDV therapy. The RDV data currently available are still controversial, however, dozens of clinical studies are currently using this drug as an alternative treatment for COVID-19, possibly further elucidating its effects.\nThe efficiency of favipiravir, another anti-influenza RdRp inhibitor, has also been clinically assessed and was approved for COVID-19 treatment in China, March 2020 (331, 332). An experimental study carried out with the VERO cell line showed that the drug has in vitro activity against SARS-CoV-2 (326). Aiming at comparing the effects of favipiravir and lopinavir/ritonavir, Cai et al. (333) conducted an open, non-randomized, before-after controlled study with 80 patients and found that favipiravir favored viral clearance and improved chest CT, having caused fewer adverse effects than the lopinavir/ritonavir group. Currently, 31 clinical trials using this medication are in progress.\nRegarding antivirals, type I IFN is a group of cytokines comprising the α and β subtypes, among others, with an important role in antiviral immunity that interferes with viral replication, as discussed above. Many studies have shown the protective effect of type I IFN associated with antiviral therapies for patients with SARS and MERS [reviewed by Sallard et al. (334)], which arouses the interest of the scientific community in type I IFN as a potential treatment against SARS-CoV-2 (334–337). Despite their efficacy against SARS-CoV-2 (338, 339), the results of in vitro studies using IFN-α and -β to treat COVID-19 patients remain inconclusive.\nSuch uncertain nature of the results is associated with biases present in these studies, which include limited-size sample, heterogeneous experimental designs/clinical status, and the type of IFN isoform tested. In addition, since COVID-19 treatments rarely involve monotherapy, it is difficult to assess whether the results derived from the tested IFN or the drugs used in combination (322, 323, 340–343). It is also worth mentioning that, as discussed above, type I IFN appears to exacerbate inflammation in the progression to severe COVID-19; the timing of administration and subgroups targeted for treatment with type I IFN need to be considered with caution.\nA recent retrospective multicenter cohort study of 446 Chinese patients with COVID-19 reported that among severe to critical COVID-19 patients, early administration (≤5 days after admission) of IFN-α2b decreased mortality in comparison with no admission of IFN-α2b, whereas no significant benefit was associated with IFN-α2b use in moderately ill patients. However, late use of IFN-α2b increased mortality and delayed recovery of severe to critical COVID-19 patients (344).\nZhou et al. (341), investigated the isolated effect of IFN-α in a cohort study comparing 77 patients with moderate COVID-19 treated with nebulized IFN-α2b (5 mU b.i.d.), oral arbidol (200 mg t.i.d.), or a combination of both. Although the study did not include a control group, the treatment with IFN-α2b, either containing arbidol or not, significantly reduced the duration of detectable virus in the upper respiratory tract and the circulating of inflammatory markers (IL-6 and C-reactive protein levels).\nStill, in a retrospective multicenter cohort study with 141 mild COVID-19 patients by Xu et al. (342), the arbidol/IFN-α2b combination proved more effective in accelerating pneumonia recovery than IFN-α2b monotherapy, but this was not the case for viral clearance or reducing the length of hospital stay than IFN-α2b monotherapy.\nHung et al. (322) assessed the effect of IFN-β on COVID-19 patients and found that the triple combination of IFN-β1b, lopinavir/ritonavir, and ribavirin was safer and more effective than lopinavir/ritonavir alone at alleviating symptoms, shortening the duration of viral shedding and hospital stay in patients with mild to moderate COVID-19. Similarly, an open randomized clinical trial was carried out by Danoudi-Monfared et al. (345), analyzing treatment with IFN-β-1a. The IFN group of COVID-19 patients (n=42) received IFN β-1a in addition to the protocol medications (hydroxychloroquine plus lopinavir-ritonavir or atazanavir-ritonavir) while the control group (n=39) received only the protocol medications. The IFN-β-1a-treated patients showed a significantly increased discharge rate on day 14 and decreased mortality within 28 days. A better survival rate was also observed when patients received IFN- β-1a in the early stage of the disease.\nThe COVID-19 treatment guidelines of many countries already recommend the use of IFNs α/β (335). Currently, all over the world, more than 20 clinical trials are using IFN-α and/or β alone or in association with other drugs."}

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nDue to the large amount of experimental and clinical studies assessing the effectiveness of antiviral therapy against SARS-CoV-2, we have seen the importance of this class of drugs in reducing the viral load peak at the beginning of the infection. Evidence from laboratory, animal, and clinical studies demonstrate that the use of associated or isolated antivirals can delay the progression of lung lesions and decrease the possibility of respiratory transmission of SARS-CoV-2. In this study, we selected the following most promising treatment options: lopinavir/ritonavir, arbidol, ribavirin, remdesivir, favipiravir, and type I IFN.\nIn the context of discovering new drugs, it is efficient to test the efficacy of existing antiviral drugs regarding the treatment of related viral infections. After the emergence of SARS in 2003, the screening of approved drugs identified an effective SARS-CoV-2 antiviral-drug candidate: the combination of the human immunodeficiency virus (HIV) protease inhibitors lopinavir and ritonavir. However, lopinavir has insufficient oral bioavailability for significant therapeutic activity due to rapid catabolism by the cytochrome P450 enzyme system. Thus, ritonavir is a cytochrome P450 and glycoproteins inhibitor, which increases the lopinavir plasma half-life, enhancing the pharmacokinetic and pharmacodynamic activities against the viral HIV-protease (303).\nChu et al. (304) described the possible mechanism of action of these drugs on SARS-CoV-1, suggesting that they act by inhibiting intracellular viral multiplication, preventing the action of the protease enzyme, which leads to the formation of an immature and less infectious virus with no ability to replicate.\nChoy et al. (305) were successful at demonstrating the antiviral effect of lopinavir against SARS-CoV-2, but this was not the case for ritonavir. In turn, Kang et al. (306) found a lower viral load in infected SARS-CoV-2 Vero cells treated with lopinavir/ritonavir in relation to the untreated infected control. Although no consensus has been reached on its efficacy, dosage, or administration period, the literature includes some case reports, case series, and observational studies reporting a protective effect of the lopinavir/ritonavir combination in COVID-19 patients (110, 307–312).\nConversely, Cao et al. (313) conducted a controlled open‐label study with 199 hospitalized severe COVID‐19 patients randomly divided into two groups: a standard care group and a lopinavir/ritonavir treatment group (400 mg/100 mg). No benefit was observed in the lopinavir/ritonavir treatment group, showing no significant results for faster clinical improvement, lower mortality, or decreased viral RNA detectability. Although there are 85 clinical trials in progress testing lopinavir/ritonavir associated with other drugs on SARS-CoV-2 and/or COVID-19, WHO stopped the study of lopinavir/ritonavir in the Solidarity Trial.\nDeng et al. (312) have studied the association of lopinavir/ritonavir with arbidol treatment and demonstrated a significant improvement in COVID-19 patients compared with a group treated only with lopinavir/ritonavir. Arbidol (umifenovir) is a broad-spectrum antiviral and immunomodulatory compound used to treat influenza and many other viruses (314). Analyses of molecular dynamics and structure-guided drug-binding have suggested an efficiency of arbidol at blocking or hampering the trimerization of the SARS-CoV-2 spike glycoprotein, in addition to inhibiting virus-cell interactions, which supports the potential use of arbidol to treat COVID-19 (315).\nChen et al. (316) demonstrated that arbidol therapy was able to shorten the course of the disease and promote clinical improvement, resulting in low fever and improvements in dry cough without side effects faster than the control group. Zhu et al. (317) also demonstrated the effects of arbidol by retrospectively analyzing the clinical data from 50 COVID-19 patients. The study demonstrated that the use of arbidol monotherapy, without association with other drugs, was more effective than the treatment with lopinavir/ritonavir, showing clinical improvement of the disease, presenting a total elimination of viral load over a shorter duration; in addition, no fever or ARDS were reported compared with those in the lopinavir/ritonavir group.\nRibavirin is another antiviral drug used in association with lopinavir/ritonavir to treat SARS-CoV-1 and was able to reduce viral load, risk of adverse clinical outcomes, ARDS, or death in SARS patients (304, 318). Ribavirin has a broad antiviral spectrum as it is a nucleotide analog that competes for the active site of RdRp, a crucial enzyme in the life cycle of RNA viruses, inhibiting viral replication and transcription (221, 319, 320).\nElfiky (320) conducted an in silico study demonstrating that ribavirin and other antivirals such as sofosbuvir can strongly bind to coronavirus RdRp, preventing the transcription of new copies of viral RNA. Only a few clinical studies have investigated the effect of ribavirin on COVID-19 patients, with the studies available generally focusing on the association of ribavirin and other therapeutic schemes (321–323). Nevertheless, China’s government (324) has recommended the use of ribavirin in COVID-19 patients.\nRemdesivir (RDV) is also among the several potential drugs tested for SARS-CoV-2 treatment. Originally developed to treat Ebola virus infection, RDV is active against RNA viruses from different families, including Coronaviridae (e.g., SARS-CoV-1 and MERS-CoV) (325). RDV showed an in vitro effective antiviral activity against SARS-CoV-2 (326). Grein et al. (327) conducted a cohort study with 53 COVID-19 patients treated with RDV and found that 68% of them had improved oxygen-support class, whereas 57% of the patients receiving mechanical ventilation were extubated. Overall mortality reached 13% over a median follow-up of 18 days, however, viral load data were not collected to confirm the antiviral effects of RDV. The biggest issue with this study is that the authors did not include a group without RDV, which hampers the performance of comparative statistical analyses to prove whether the data found resulted from the treatment with RDV.\nAnother double-blind, randomized, placebo-controlled trial of intravenous RDV conducted in adults hospitalized with COVID-19 with evidence of lower respiratory tract involvement was performed in different parts of the world (328). The study of Beigel and colleagues (328) enrolled 1,063 COVID19 pneumonia patients, 538 of whom were assigned to the treatment with RDV and 521 to a placebo, showed the effectiveness of RDV in treating COVID-19 patients. The drug was superior to the placebo in reducing the recovery time in hospitalized COVID-19 patients and decreased the mortality rate in the RDV group, however, this result did not reach statistical significance.\nAntionori et al. (329), analyzing patients with severe COVID-19 pneumonia in an intensive care unit (ICU) who were treated for 10 days with RDV, found that on the 28th day, 38.9% showed improvement, 16.7% were still on mechanical ventilation, and 44.4% died. The data suggest that this treatment can benefit hospitalized patients who are not in the ICU, where the clinical result was better and adverse events are observed less frequently.\nAlternatively, the randomized, double-blind, placebo-controlled, multicenter trial with 273 ill individuals performed by Wang et al. revealed that RDV intravenous administration was well-tolerated in COVID-19 patients. However, the authors did not find any clinical improvement or significant antiviral effect. Goldman et al. (330), in another phase 3 clinical trial on 397 patients with severe COVID-19 without mechanical ventilation support, also did not find differences between 5-day and 10-day courses of RDV therapy. The RDV data currently available are still controversial, however, dozens of clinical studies are currently using this drug as an alternative treatment for COVID-19, possibly further elucidating its effects.\nThe efficiency of favipiravir, another anti-influenza RdRp inhibitor, has also been clinically assessed and was approved for COVID-19 treatment in China, March 2020 (331, 332). An experimental study carried out with the VERO cell line showed that the drug has in vitro activity against SARS-CoV-2 (326). Aiming at comparing the effects of favipiravir and lopinavir/ritonavir, Cai et al. (333) conducted an open, non-randomized, before-after controlled study with 80 patients and found that favipiravir favored viral clearance and improved chest CT, having caused fewer adverse effects than the lopinavir/ritonavir group. Currently, 31 clinical trials using this medication are in progress.\nRegarding antivirals, type I IFN is a group of cytokines comprising the α and β subtypes, among others, with an important role in antiviral immunity that interferes with viral replication, as discussed above. Many studies have shown the protective effect of type I IFN associated with antiviral therapies for patients with SARS and MERS [reviewed by Sallard et al. (334)], which arouses the interest of the scientific community in type I IFN as a potential treatment against SARS-CoV-2 (334–337). Despite their efficacy against SARS-CoV-2 (338, 339), the results of in vitro studies using IFN-α and -β to treat COVID-19 patients remain inconclusive.\nSuch uncertain nature of the results is associated with biases present in these studies, which include limited-size sample, heterogeneous experimental designs/clinical status, and the type of IFN isoform tested. In addition, since COVID-19 treatments rarely involve monotherapy, it is difficult to assess whether the results derived from the tested IFN or the drugs used in combination (322, 323, 340–343). It is also worth mentioning that, as discussed above, type I IFN appears to exacerbate inflammation in the progression to severe COVID-19; the timing of administration and subgroups targeted for treatment with type I IFN need to be considered with caution.\nA recent retrospective multicenter cohort study of 446 Chinese patients with COVID-19 reported that among severe to critical COVID-19 patients, early administration (≤5 days after admission) of IFN-α2b decreased mortality in comparison with no admission of IFN-α2b, whereas no significant benefit was associated with IFN-α2b use in moderately ill patients. However, late use of IFN-α2b increased mortality and delayed recovery of severe to critical COVID-19 patients (344).\nZhou et al. (341), investigated the isolated effect of IFN-α in a cohort study comparing 77 patients with moderate COVID-19 treated with nebulized IFN-α2b (5 mU b.i.d.), oral arbidol (200 mg t.i.d.), or a combination of both. Although the study did not include a control group, the treatment with IFN-α2b, either containing arbidol or not, significantly reduced the duration of detectable virus in the upper respiratory tract and the circulating of inflammatory markers (IL-6 and C-reactive protein levels).\nStill, in a retrospective multicenter cohort study with 141 mild COVID-19 patients by Xu et al. (342), the arbidol/IFN-α2b combination proved more effective in accelerating pneumonia recovery than IFN-α2b monotherapy, but this was not the case for viral clearance or reducing the length of hospital stay than IFN-α2b monotherapy.\nHung et al. (322) assessed the effect of IFN-β on COVID-19 patients and found that the triple combination of IFN-β1b, lopinavir/ritonavir, and ribavirin was safer and more effective than lopinavir/ritonavir alone at alleviating symptoms, shortening the duration of viral shedding and hospital stay in patients with mild to moderate COVID-19. Similarly, an open randomized clinical trial was carried out by Danoudi-Monfared et al. (345), analyzing treatment with IFN-β-1a. The IFN group of COVID-19 patients (n=42) received IFN β-1a in addition to the protocol medications (hydroxychloroquine plus lopinavir-ritonavir or atazanavir-ritonavir) while the control group (n=39) received only the protocol medications. The IFN-β-1a-treated patients showed a significantly increased discharge rate on day 14 and decreased mortality within 28 days. A better survival rate was also observed when patients received IFN- β-1a in the early stage of the disease.\nThe COVID-19 treatment guidelines of many countries already recommend the use of IFNs α/β (335). Currently, all over the world, more than 20 clinical trials are using IFN-α and/or β alone or in association with other drugs."}