Emerging treatments
Interleukin-6 (IL-6) inhibitors
IL-6 inhibitors inhibit IL-6-mediated signaling by competitively binding to IL-6 receptors. IL-6 is a proinflammatory cytokine. These drugs (e.g., tocilizumab, sarilumab, siltuximab) are being trialed in patients for the treatment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-induced cytokine release syndrome. They are already approved in some countries for certain conditions, but are off-label for this indication. The UK National Institute for Health and Care Excellence recommends a single dose of tocilizumab in hospitalized adults if all of the following conditions apply: they are having or have completed a course of corticosteroids such as dexamethasone (unless they cannot have corticosteroids); they have not had another IL-6 inhibitor during this admission; there is no evidence of a bacterial or viral infection (other than SARS-CoV-2) that might be worsened by tocilizumab; AND they either need supplemental oxygen and have a C-reactive protein level of ≥75 mg/L, OR they are within 48 hours of starting high-flow nasal oxygen, continuous positive airway pressure, noninvasive ventilation, or invasive mechanical ventilation.[538] Consider tocilizumab for children and young people who have severe disease or pediatric inflammatory multisystem syndrome only if they are ages 1 year and over, and only in the context of a clinical trial. Sarilumab may be considered an alternative option in adults only if tocilizumab cannot be used or is unavailable (use the same eligibility criteria as those for tocilizumab). These recommendations are based on data from the UK RECOVERY and REMAP-CAP trials (see below). The US National Institutes of Health guidelines panel recommends a single dose of tocilizumab, in combination with dexamethasone (or a suitable alternative corticosteroid), in certain hospitalized adults who are exhibiting rapid respiratory decompensation due to progressive COVID-19.[501] This includes: recently hospitalized patients (e.g., within 3 days) who have been admitted to the intensive care unit within the prior 24 hours and who require invasive mechanical ventilation, noninvasive mechanical ventilation, or high-flow nasal oxygen; OR recently hospitalized patients, not in the intensive care unit, with rapidly increasing oxygen needs who require noninvasive mechanical ventilation or high-flow nasal oxygen and have significantly increased markers of inflammation (e.g., C-reactive protein level is ≥75 mg/L). Some panel members also recommend tocilizumab in patients who are exhibiting rapidly increasing oxygen needs while on a corticosteroid and have a C-reactive protein level ≥75 mg/L but who do not yet require noninvasive mechanical ventilation or high-flow nasal oxygen. However, there is insufficient evidence to specify which of these patients would benefit from the addition of tocilizumab. Tocilizumab should be given only in combination with a corticosteroid. There are insufficient data for the panel to recommend either for or against the use of sarilumab for hospitalized patients who are within 24 hours of admission to the intensive care unit and who require invasive mechanical ventilation, noninvasive ventilation, or high-flow oxygen. The panel recommends against the use of siltuximab, except in the context of a clinical trial. In children, there are insufficient data to recommend either for or against the use of tocilizumab, including those with multisystem inflammatory syndrome. The panel recommends against the use of sarilumab in hospitalized children, except in the context of a clinical trial. The Infectious Diseases Society of America recommends tocilizumab in hospitalized adults with progressive severe or critical disease who have elevated markers of systemic inflammation, in addition to standard of care (i.e., corticosteroids), rather than standard of care alone.[770] This recommendation is conditional, based on low-certainty evidence. Patients, particularly those who respond to corticosteroids alone, who put a high value on avoiding possible adverse events of tocilizumab and a low value on the uncertain mortality reduction, would reasonably decline tocilizumab. Evidence is emerging. A Cochrane living systematic review found that tocilizumab reduced all-cause mortality at day 28, and probably resulted in slightly fewer serious adverse events compared with standard care alone or placebo. The evidence suggests uncertainty around the effect on mortality after day 60. However, tocilizumab probably results in little or no increase in clinical improvement at day 28 (i.e., hospital discharge or improvement measured by trialist-defined scales). The impact of tocilizumab on other outcomes is uncertain. More data are needed to be able to identify which patients are more likely to benefit from this treatment. Evidence for an effect of sarilumab is uncertain.[826] A meta-analysis (as of 22 February 2021) found that use of IL-6 inhibitors is associated with a clinically meaningful improvement in 28-day mortality for patients with severe disease. The results were heavily influenced by the RECOVERY trial, which accounted for over three-quarters of the overall study weighting in the analysis. The benefits of IL-6 inhibitors over the medium- to long-term remain unknown.[827] However, other meta-analyses, which included the RECOVERY and REMAP-CAP trials, found that tocilizumab does not provide a survival benefit but does reduce the risk of mechanical ventilation and intensive care unit admission. Only the REMAP-CAP and RECOVERY trials, with the majority of their patients on concomitant corticosteroids, showed lower 30-day mortality.[828][829] A living systematic review and network meta-analysis found that IL-6 inhibitors are likely to reduce the need for mechanical ventilation (moderate-certainty evidence) and may reduce the duration of hospitalization (low-certainty evidence) compared with standard care.[767][825] Data from the UK RECOVERY trial found that tocilizumab reduced 28-day mortality compared with usual care in patients who required oxygen and had evidence of inflammation. The results showed that 31% of patients in the tocilizumab group died within 28 days compared with 35% in the usual care group, a 15% reduction in relative mortality. Tocilizumab also increased the probability of discharge alive within 28 days from 50% to 57%. These benefits were seen regardless of the level of respiratory support, and were additional to the benefits of corticosteroids.[830] Data from the REMAP-CAP trial showed more organ support-free days and a reduction in mortality when IL-6 inhibitors were given to critically ill patients receiving organ support in the intensive care unit within 24 hours of admission, compared with standard of care (including corticosteroids in the majority of patients).[831] A randomized controlled phase 3 trial found that there was no observed benefit of sarilumab in patients with severe or critical disease who were receiving supplemental oxygen and the local standard of care, compared with placebo.[832] Evidence is conflicting, and it has been suggested that the value of IL-6 inhibitor treatment may be dependent on the timing of treatment and the concomitant use of corticosteroids.[833] A score to assist clinicians in identifying patients who are likely to progress to mechanical ventilation or death early after tocilizumab administration, so that they can be selected for rescue therapies, is in development.[834] Tocilizumab should be avoided in patients who are significantly immunocompromised.[501] Consult local drug formulary for information about contraindications, cautions, adverse effects, and drug interactions before prescribing these drugs.
Remdesivir
Remdesivir is an investigational broad-spectrum antiviral agent that inhibits RNA-dependent RNA polymerase. It is approved in many countries for the treatment of COVID-19. In the UK and Europe, remdesivir has been conditionally approved in adolescents (≥12 years of age who weigh at least 40 kg) and adults with pneumonia who require supplemental oxygen (low- or high-flow oxygen or other noninvasive ventilation at start of treatment).[835] In the US, remdesivir has been approved for the treatment of adolescents (≥12 years of age who weigh at least 40 kg) and adults who require hospitalization, and has emergency-use authorization for use in children.[836] The World Health Organization recommends against the use of remdesivir in hospitalized patients in addition to standard care, regardless of disease severity.[722][764][765] This weak or conditional recommendation is based on a systematic review and network meta-analysis of four randomized trials with 7333 hospitalized patients, and included the NIAID-ACTT-1 trial (on which the original US approval of remdesivir was based) and the WHO Solidarity trial. There is currently no evidence that remdesivir improves patient outcomes such as time to clinical improvement, the need for mechanical ventilation, or mortality. However, the meta-analysis did not prove that remdesivir has no benefit.[764][765] The WHO Solidarity trial found that remdesivir appears to have little or no effect on hospitalized patients, as indicated by overall mortality, initiation of ventilation, and duration of hospital stay.[837] Another living systematic review and network meta-analysis found that remdesivir may reduce the need for mechanical ventilation (low-certainty evidence) compared with standard of care.[767][825] The UK National Institute for Health and Care Excellence recommends remdesivir in adults and children ≥12 years of age and ≥40 kg who are in hospital and on supplemental oxygen but not on invasive mechanical ventilation.[538] Complete the 5-day course of treatment if remdesivir has been started and there is subsequent progression to invasive mechanical ventilation. The US National Institutes of Health guidelines panel recommends remdesivir in hospitalized adults who require supplemental oxygen.[501] It may be given alone (e.g., for patients who require minimal supplemental oxygen) or in combination with dexamethasone (e.g., for patients who require increasing amounts of supplemental oxygen). The panel also recommends remdesivir, in combination with dexamethasone, in hospitalized patients who require high-flow oxygen or noninvasive ventilation. It does not recommend remdesivir in patients who require invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO). The panel acknowledges that remdesivir may also be appropriate in hospitalized patients who do not require oxygen, but who are at high risk of disease progression. The recommended treatment course is 5 days or until hospital discharge, whichever comes first. Some experts recommend a 10-day course in patients who have not shown substantial clinical improvement by day 5. In children, the panel recommends remdesivir in those who are hospitalized, are ages ≥12 years, have risk factors for severe disease, and have an emergent or increasing need for supplemental oxygen. The panel recommends remdesivir in hospitalized children ages ≥16 years who have an emergent or increasing need for supplemental oxygen, regardless of whether they have risk factors for severe disease. The panel recommends considering remdesivir in hospitalized children of all ages who have an emergent or increasing need for supplemental oxygen, in consultation with a pediatric infectious disease specialist. The Infectious Diseases Society of America recommends remdesivir in hospitalized patients with severe disease over no antiviral treatment, based on moderate-certainty evidence.[770] The recommended treatment course is 5 days in patients on oxygen, and 10 days in patients on mechanical ventilation or ECMO. The panel suggests against the routine use of remdesivir in hospitalized patients who do not require oxygen and have an oxygen saturation >94% on room air, based on very low-certainty evidence. There are conflicting recommendations across international guidelines about the use of remdesivir, so it is important that you check local guidance and protocols. Consult local drug formulary for information about contraindications, cautions, adverse effects, and drug interactions before prescribing this drug.
Casirivimab/imdevimab
Casirivimab and imdevimab are intravenous investigational neutralizing human immunoglobulin G-1 monoclonal antibodies with activity against SARS-CoV-2. The two antibodies bind to nonoverlapping epitopes of the receptor-binding domain of the spike protein to block virus entry into host cells. Casirivimab/imdevimab (formerly known as REGN-COV2) has been granted an emergency-use authorization in the US for the treatment of mild to moderate disease in children and adults.[838] The US emergency-use authorization covers patients with positive results of direct viral testing who are 12 years of age and older weighing at least 40 kg, and who are at high risk for progressing to severe disease and/or hospitalization. This includes patients who are 65 years of age or older, or who have certain chronic medical conditions. The European Medicines Agency has issued advice that casirivimab/imdevimab may be used in patients ages 12 years and older who do not require supplemental oxygen and who are at high risk of progressing to severe disease; however, the agency is yet to issue a marketing authorization.[839] The US National Institutes of Health guidelines panel recommends casirivimab/imdevimab for the treatment of outpatients with mild to moderate disease who are at high risk of clinical progression, as defined by the emergency-use authorization criteria.[501] Treatment should be started as soon as possible after the patient receives a positive test result and within 10 days of symptom onset. The panel recommends against the use of monoclonal antibodies in hospitalized patients, except in the context of a clinical trial. However, their use may be considered in patients with mild to moderate disease who are hospitalized for a reason other than COVID-19 but who otherwise meet the emergency-use authorization criteria. In children, there are insufficient data to recommend either for or against the use of monoclonal antibody products in those who are not hospitalized but have risk factors for severe disease. However, they may be considered on a case-by-case basis for nonhospitalized children who meet emergency-use authorization criteria for high risk of severe disease (especially those who meet more than one criterion or are ages ≥16 years) in consultation with a pediatric infectious disease specialist. The Infectious Diseases Society of America suggests casirivimab/imdevimab in ambulatory patients with mild to moderate disease who are at high risk for progression to severe disease rather than no neutralising antibodies, based on low-certainty evidence.[770] Patients with mild to moderate disease who are at high risk of progression to severe disease admitted to the hospital for reasons other than COVID-19 may also receive casirivimab/imdevimab. There are limited data on efficacy in high-risk patients between 12 and 18 years of age. Evidence is emerging. Emergency-use authorization was based on a randomized, double-blind, placebo-controlled trial in nonhospitalized adults with mild to moderate symptoms that found that casirivimab/imdevimab reduced hospitalization or emergency department visits in patients at high risk for disease progression within 28 days after treatment, when compared with placebo. This study is yet to be published.[838] An interim analysis of an ongoing, randomized, double-blind, phase 1-3 trial in nonhospitalized patients found that casirivimab/imdevimab reduced viral load from baseline through to day 7, with a greater effect in patients whose immune response had not yet been initiated or who had a high viral load at baseline.[840] Casirivimab/imdevimab is not authorized for use in hospitalized patients or those who require oxygen as it has not shown benefit in these patients. Further enrollment of patients requiring high-flow oxygen or mechanical ventilation has been placed on hold due to a potential safety signal and an unfavorable risk/benefit profile at this time. However, enrollment of hospitalized patients requiring either no or low-flow oxygen is being continued.[841] Consult local drug formulary for information about contraindications, cautions, adverse effects, and drug interactions before prescribing this drug. Circulating SARS-CoV-2 variants may be associated with resistance to monoclonal antibodies. Consult local guidance for details regarding specific variants and resistance.
Bamlanivimab/etesevimab
Bamlanivimab (formerly known as LY-CoV555) and etesevimab (formerly known as LY-CoV016) are intravenous investigational neutralizing human immunoglobulin G-1 monoclonal antibodies with activity against SARS-CoV-2. The two antibodies bind to different, but overlapping, epitopes of the receptor-binding domain of the spike protein to block virus entry into host cells. Bamlanivimab/etesevimab has been granted an emergency-use authorization in the US for the treatment of mild to moderate disease in children and adults.[842] The US emergency-use authorization for bamlanivimab monotherapy has been revoked.[843] The US emergency-use authorization covers patients with positive results of direct viral testing who are 12 years of age and older weighing at least 40 kg, and who are at high risk for progressing to severe disease and/or hospitalization. This includes patients who are 65 years of age or older, or who have certain chronic medical conditions. The European Medicines Agency has issued advice that bamlanivimab/etesevimab may be used in patients ages 12 years and older who do not require supplemental oxygen and who are at high risk of progressing to severe disease. The agency is yet to issue a marketing authorization, but has started a rolling review of the data. The agency also concluded that despite uncertainties around the benefits of bamlaniviamab monotherapy, it can be considered a treatment option for this indication.[844] The US National Institutes of Health guidelines panel recommends bamlanivimab/etesevimab for the treatment of outpatients with mild to moderate disease who are at high risk of clinical progression, as defined by the emergency-use authorization criteria.[501] Treatment should be started as soon as possible after the patient receives a positive test result and within 10 days of symptom onset. The panel recommends against the use of monoclonal antibodies in hospitalized patients, except in the context of a clinical trial. However, their use may be considered in patients with mild to moderate disease who are hospitalized for a reason other than COVID-19 but who otherwise meet the emergency-use authorization criteria. The panel recommends against the use of bamlanivimab monotherapy as clinical outcome data are limited and there are concerns regarding decreased susceptibility of variants. In children, there are insufficient data to recommend either for or against the use of monoclonal antibody products in those who are not hospitalized but have risk factors for severe disease. However, they may be considered on a case-by-case basis for nonhospitalized children who meet emergency-use authorization criteria for high risk of severe disease (especially those who meet more than one criterion or are ages ≥16 years) in consultation with a pediatric infectious disease specialist. The Infectious Diseases Society of America suggests bamlanivimab/etesevimab in ambulatory patients with mild to moderate disease who are at high risk for progression to severe disease rather than no neutralizing antibodies, based on low-certainty evidence.[770] Patients with mild to moderate disease who are at high risk of progression to severe disease admitted to the hospital for reasons other than COVID-19 may also receive bamlanivimab/etesevimab. There are limited data on efficacy in high-risk patients between 12 and 18 years of age. The panel recommends against the use of bamlanivimab monotherapy in hospitalized patients with severe disease, based on moderate-certainty evidence. Evidence is emerging. Among patients with mild to moderate disease, treatment with bamlanivimab/etesevimab was associated with a significant reduction in viral load at day 11 compared with placebo; however, no significant difference in viral load reduction was observed with bamlanivimab monotherapy.[845] Consult local drug formulary for information about contraindications, cautions, adverse effects, and drug interactions before prescribing this drug. Circulating SARS-CoV-2 variants may be associated with resistance to monoclonal antibodies. Consult local guidance for details regarding specific variants and resistance.
Convalescent plasma
Convalescent plasma is a blood product that contains antibodies to SARS-CoV-2 from patients who have recovered. High-titer convalescent plasma (i.e., plasma with high SARS-CoV-2 antibody titers) has been granted an emergency-use authorization in the US for the treatment of hospitalized patients early in the disease course, and to those hospitalized patients who have impaired humoral immunity and cannot produce an adequate antibody response. Low-titer convalescent plasma is no longer authorized.[846] It has not been authorized for this indication in the UK or Europe. UK guidance recommends that convalescent plasma should not be used in the management of hospitalized patients with suspected or confirmed infection.[847] This recommendation is based on data from the UK RECOVERY and REMAP-CAP trials. Preliminary data (yet to be peer reviewed) from the UK RECOVERY trial found that high-titer convalescent plasma did not improve survival or other prespecified clinical outcomes among hospitalized patients.[848] The US National Institutes of Health guidelines panel recommends against the use of low-titer convalescent plasma.[501] There are insufficient data for the panel to recommend either for or against the use of high-titer convalescent plasma in hospitalized patients with impaired immunity. The panel recommends against the use of high-titer convalescent plasma in hospitalized patients who do not have impaired immunity and who do not require mechanical ventilation, except in the context of a clinical trial. The panel recommends against the use of convalescent plasma in hospitalized patients who do not have impaired immunity and who require mechanical ventilation. There are insufficient data for the panel to recommend either for or against the use of high-titer convalescent plasma in nonhospitalized patients, except in the context of a clinical trial. In children, the panel recommends against the use of convalescent plasma in those who are mechanically ventilated. The panel recommends against the use of convalescent plasma in hospitalized children who do not require mechanical ventilation, except in the context of a clinical trial. High-titer convalescent plasma may be considered on a case-by-case basis for hospitalized children who meet the emergency-use authorization criteria for its use, in consultation with a pediatric infectious disease specialist. The Infectious Diseases Society of America suggests against the use of convalescent plasma in hospitalized patients, based on low-certainty evidence.[770] The guideline panel recommends convalescent plasma in ambulatory patients with mild to moderate disease only in the context of a clinical trial. Evidence is emerging. Emergency-use authorization was based on the preprint (not peer reviewed) publication of an open-label, multicenter, expanded access program study of over 35,000 patients that found convalescent plasma lowered 7-day mortality by 9% in hospitalized patients when given within 3 days of diagnosis, and by 12% when given 4 or more days later.[849] A meta-analysis and systematic review of four peer-reviewed randomized controlled trials (1060 patients) and six unpublished randomized controlled trials (10,722 patients) found that treatment with convalescent plasma was not significantly associated with a decrease in all-cause mortality (or any benefit for other outcomes) compared with placebo or standard of care, based on low- to moderate-certainty evidence.[850] A randomized, double-blind, placebo-controlled trial in older patients with mild disease who received convalescent plasma within 72 hours after the onset of symptoms found that early administration reduced the progression to severe disease.[851] A Cochrane review found that currently available evidence on the safety and efficacy of convalescent plasma for the treatment of hospitalized patients is of low or very low certainty.[852] A National Institutes of Health clinical trial evaluating the safety and efficacy of convalescent plasma in treating emergency department patients who developed mild to moderate symptoms has been halted. An interim analysis of the trial data determined that while convalescent plasma caused no harm, it was unlikely to benefit this group of patients.[853]
Baricitinib
Baricitinib is an oral Janus kinase inhibitor. It is thought to prevent the dysregulated production of proinflammatory cytokines in patients with severe or critical disease. Baricitinib is already approved in some countries for certain conditions. It has been granted an emergency-use authorization in the US, in combination with remdesivir, for the treatment of suspected or confirmed disease in hospitalized children ages 2 years and older and adults who require supplemental oxygen, invasive mechanical ventilation, or extracorporeal membrane oxygenation.[854] It has not been authorized for this indication in the UK or Europe; however, the European Medicines Agency is currently evaluating its use in hospitalized patients from 10 years of age who require supplemental oxygen.[855] The US National Institutes of Health guidelines panel states that there are insufficient data to recommend either for or against the use of baricitinib, in combination with remdesivir, for the treatment of hospitalized patients in cases where corticosteroids can be used instead.[501] In rare cases where corticosteroids cannot be used, the panel recommends baricitinib in combination with remdesivir for the treatment of hospitalized, nonintubated patients who require oxygen supplementation. The panel recommends against the use of baricitinib monotherapy, except in the context of a clinical trial. There are insufficient data to recommend either for or against the use of baricitinib in combination with corticosteroids. In children, there are insufficient data for the panel to recommend either for or against the use of baricitinib, in combination with remdesivir, in hospitalized children in whom corticosteroids cannot be used. The Infectious Diseases Society of America recommends baricitinib with remdesivir in hospitalized patients with severe disease who cannot receive corticosteroids because of a contraindication, rather than remdesivir alone.[770] The combination should only be given with a corticosteroid in the context of a clinical trial. Evidence is emerging. Emergency-use authorization was based on a randomized, double-blind, placebo-controlled trial that found baricitinib plus remdesivir reduced time to recovery (defined as either being discharged from the hospital, or being hospitalized but not requiring supplemental oxygen and no longer requiring ongoing medical care) within 29 days after initiating treatment compared with patients who received placebo plus remdesivir. The median time to recovery was 7 days for baricitinib plus remdesivir and 8 days for placebo plus remdesivir.[856] A living systematic review and network meta-analysis found that Janus kinase inhibitors may reduce the need for mechanical ventilation (low-certainty evidence) and probably reduce the duration of mechanical ventilation (moderate-certainty evidence) compared with standard care.[767][825] Consult local drug formulary for information about contraindications, cautions, adverse effects, and drug interactions before prescribing this drug.
Ivermectin
Ivermectin is a broad-spectrum antiparasitic agent. It has been shown to be effective against SARS-CoV-2 in vitro.[857] Ivermectin is already approved in some countries for parasitic infections, but is off-label for this indication. The European Medicines Agency does not recommend ivermectin for the treatment or prevention of COVID-19 outside of clinical trials.[858] The World Health Organization does not recommend ivermectin except in the context of a clinical trial.[722] This recommendation applies to patents with any disease severity and any duration of symptoms. There is insufficient evidence to be clear to what extent, if any, ivermectin is helpful or harmful in treating COVID-19.[764][765] For most key outcomes, including mortality, mechanical ventilation, hospital admission, duration of hospitalization, and viral clearance, the evidence is of very low certainty. The US National Institutes of Health guidelines panel states that there is currently insufficient evidence to recommend either for or against the use of ivermectin.[501] The Infectious Diseases Society of America recommends against the use of ivermectin in outpatients and hospitalized patients outside of the context of a clinical trial, adding that more trials of sufficient design are needed.[770] Evidence is emerging. A meta-analysis of 18 randomized controlled trials found statistically significant reductions in mortality, time to clinical recovery, and time to viral clearance.[859] A systematic review and meta-analysis found that adding ivermectin to usual care led to significant clinical improvement and a significant reduction in all-cause mortality compared with usual care; however, the quality of evidence was very low.[860] A meta-analysis of six randomized controlled trials found a preliminary positive effect on mortality associated with use in hospitalized patients. The authors concluded that this effect warrants further appropriately designed, large-scale randomized controlled trials. The meta-analysis was limited by a small number of patients included with a significant risk of biases in the majority of included trials.[861] A living systematic review and network meta-analysis found that studies on ivermectin for prophylaxis have been small and it remains very uncertain whether ivermectin reduces the risk of infection. Evidence for the effects of ivermectin on mortality is of very low certainty.[862] Consult local drug formulary for information about contraindications, cautions, adverse effects, and drug interactions before prescribing this drug.
Anakinra
Anakinra is an intravenous/subcutaneous interleukin-1 inhibitor. It is being trialed in patients for the treatment of SARS-CoV-2-induced cytokine release syndrome. Anakinra is already approved in some countries for certain conditions, but is off-label for this indication. The US National Institutes of Health guidelines panel states that there is currently insufficient evidence to recommend either for or against the use of anakinra.[501] The UK National Institute for Health and Care Excellence states that there is no evidence available to determine whether anakinra is effective, safe, or cost-effective for treating adults and children with secondary hemophagocytic lymphohistiocytosis triggered by SARS-CoV-2 or a similar coronavirus.[863] Evidence is limited. A small retrospective study found that the addition of high-dose anakinra to noninvasive ventilation and standard care (including hydroxychloroquine and lopinavir/ritonavir) in patients with moderate to severe acute respiratory distress syndrome and hyperinflammation was associated with a higher survival rate at 21 days.[864] A large retrospective study found that anakinra was associated with a significant reduction in mortality in hospitalized patients compared with patients who did not receive interleukin inhibitors.[865] A small prospective cohort study found that anakinra significantly reduced the need for invasive mechanical ventilation and mortality in patients with severe disease.[866] A small retrospective case series found that anakinra could be beneficial in patients with cytokine release syndrome when initiated early after the onset of acute hypoxic respiratory failure.[867] A phase 3 trial comparing anakinra with optimized standard of care in hospitalized patients has been suspended due to excess mortality in the intervention arm.[868] An open-label randomized controlled trial found that anakinra did not improve outcomes in patients with mild to moderate disease.[869] Consult local drug formulary for information about contraindications, cautions, adverse effects, and drug interactions before prescribing this drug.
Regdanvimab
Regdanivimab (formerly known as CT-P59) is an investigational neutralizing monoclonal antibody with activity against SARS-CoV-2. Regdanvimab has been granted a conditional marketing authorization in South Korea for the treatment of adults with mild symptoms who are ages ≥60 years or have at least one underlying medical condition, and all adults with moderate symptoms. The European Medicines Agency recommends that regdanvimab can be used for the treatment of confirmed COVID-19 in adult patients who do not require supplemental oxygen therapy and who are at high risk of progressing to severe disease.[870] Evidence is limited. According to a press release from the manufacturer, regdanivimab reduced progression from mild-moderate to severe disease by 50%, and from moderate to severe disease by 68%. However, results from the phase 2/3 trial are yet to be published.[871] Regdanivimab has also demonstrated neutralizing capability against key emerging mutations, including the B.1.1.7 variant.[872]
Intravenous immune globulin
Intravenous immune globulin (IVIG) is a blood product prepared from serum pooled from healthy donors. It has an immunomodulatory effect that suppresses a hyperactive immune response. IVIG is already approved in some countries for certain conditions, but is off-label for this indication. The US National Institutes of Health guidelines panel recommends against the use of non-SARS-CoV-2-specific IVIG except in the context of a clinical trial.[501] Evidence is limited. A retrospective study of 58 patients with severe disease found that IVIG, when used as an adjuvant treatment within 48 hours of admission, may reduce the use of mechanical ventilation, reduce hospital/intensive care unit stay, and reduce 28-day mortality; however, this study had several limitations.[873] There is currently insufficient evidence to recommend IVIG.[874] Consult local drug formulary for information about contraindications, cautions, adverse effects, and drug interactions before prescribing this drug.
Stem cell therapy
Mesenchymal stem cells are an investigational product and have been studied for their immunomodulatory properties. It is thought that they can reduce the pathologic changes that occur in the lungs, and inhibit the cell-mediated immune inflammatory response.[875] Mesenchymal stem cells are not approved for this indication. The US National Institutes of Health guidelines panel recommends against the use of mesenchymal stem cells except in the context of a clinical trial.[501] Evidence is limited. Remestemcel-L (ex vivo cultured adult human mesenchymal stem cells from the bone marrow of healthy adult donors) is currently in phase 3 trials for the treatment of moderate to severe acute respiratory distress syndrome in ventilator-dependent patients. An interim analysis of data found that the trial is not likely to meet its 30-day mortality reduction end point and has stopped enrollment, although the trial will be completed with the patients currently enrolled, with follow-up as planned.[876]
Interferons
Interferons are a family of cytokines with antiviral properties. Interferons are already approved in some countries for certain conditions, but are off-label for this indication. The US National Institutes of Health guidelines panel recommends against the use of interferons for the treatment of severe or critically ill patients except in the context of a clinical trial.[501] Evidence is limited. The WHO Solidarity trial found that interferon beta-1a appears to have little or no effect on hospitalized patients, as indicated by overall mortality, initiation of ventilation, and duration of hospital stay.[837] A randomized, placebo-controlled, phase 2 trial found that nebulized interferon beta-1a was associated with a higher odds of clinical improvement and more rapid recovery.[877] A phase 2 trial found that peginterferon lambda reduced viral load and increased the number of participants with a negative nasopharyngeal swab at day 7 in outpatients with mild to moderate disease compared with placebo.[878][879] Consult local drug formulary for information about contraindications, cautions, adverse effects, and drug interactions before prescribing these drugs.
Vitamin D
Vitamin D supplementation has been associated with a reduced risk of acute respiratory infections such as influenza.[880][881][882][883] The US National Institutes of Health guidelines panel states that there are insufficient data to recommend either for or against vitamin D for the treatment or prevention of COVID-19.[501] The UK National Institute for Health and Care Excellence recommends vitamin D supplementation in adults (including pregnant and breastfeeding women), young people, and children over 4 years of age between October and early March (and at other times of the year if at risk of vitamin D deficiency) to maintain bone and muscle health. However, it does not recommend supplementation to solely prevent or treat COVID-19, except as part of a clinical trial.[884] Evidence is limited. There is currently no evidence to recommend vitamin D for the prophylaxis or treatment of COVID-19.[885] A meta-analysis found that there may be a potential role for vitamin D supplementation in reducing disease severity, but noted that additional evidence is required.[886] A pilot randomized controlled trial found that high-dose calcifediol significantly reduced the need for intensive care unit treatment in hospitalized patients, and may improve clinical outcomes.[887]
Vitamin C
Vitamin C supplementation has shown promise in the treatment of viral infections.[888] High-dose intravenous vitamin C is being trialed in some centers for the treatment of severe disease.[889] The US National Institutes of Health guidelines panel states that there are insufficient data to recommend either for or against vitamin C for the treatment of noncritically ill or critically ill patients.[501] Evidence is limited. There is no evidence to support or refute the use of vitamin C in the treatment of patients with COVID-19; however, several trials are ongoing.[890] A pilot randomized controlled trial found high-dose intravenous vitamin C may show potential benefit in improving oxygenation and reducing mortality in critically ill patients; however, the trial was underpowered.[891]
Colchicine
Colchicine is an anti-inflammatory agent that downregulates multiple pro-inflammatory pathways. It is thought that its inhibitory effects on neutrophil activity, cytokine generation, and the inflammation/thrombosis interface, along with an overall lack of evidence for systemic immunosuppression, make it a useful treatment.[892] Colchicine is already approved in some countries for indications such as gout and familial Mediterranean fever, but is off-label for this indication. The US National Institutes of Health guidelines panel states that there is currently insufficient evidence to recommend either for or against the use of colchicine in nonhospitalized patients.[501] The panel recommends against its use in hospitalized patients, except in the context of a clinical trial. The UK Medicines and Healthcare products Regulatory Agency states that colchicine should not be used except in the context of a clinical trial, or unless there is an additional licensed indication for its use.[893] Evidence is limited. Studies are inconclusive in patients with mild to moderate disease, and adverse effects are significant.[894] More randomized controlled trials are required. Colchicine was being studied in the RECOVERY trial; however, recruitment has now closed as an interim analysis of the trial data found no convincing evidence that further recruitment would provide conclusive proof of mortality benefit.[895] A systematic review and meta-analysis found that colchicine was associated with a reduction in disease severity and mortality, especially when given early in the course of disease (within 3-6 days from the onset of symptoms or hospital admission). However, the analysis was largely based on observational studies and only included three randomized clinical trials.[896] A living systematic review and network meta-analysis found that colchicine may reduce mortality (low-certainty evidence) and probably reduces the duration of hospitalization (low-certainty evidence) compared with standard care.[767][825] Consult local drug formulary for information about contraindications, cautions, adverse effects, and drug interactions before prescribing these drugs.
Antibiotics
Azithromycin is a macrolide antibiotic, and doxycycline is a tetracycline antibiotic. Both are approved for use in various bacterial infections. The UK Medicines and Healthcare products Regulatory Agency recommends that azithromycin and doxycycline should not be used within primary care (or hospitalized patients for azithromycin) unless there are additional indications for which their use remains appropriate.[897] The US National Institutes of Health guidelines panel recommends against the use of antibacterial therapy (e.g., azithromycin, doxycycline) in the absence of another indication.[501] Evidence does not support the use of these drugs. The UK RECOVERY trial found that azithromycin showed no significant clinical benefit (i.e., length of hospital stay, need for invasive mechanical ventilation, 28-day mortality) in hospitalized patients compared with usual standard care alone.[898] The UK PRINCIPLE trial is currently evaluating three treatment strategies in older people (people ages over 65 years, or people ages over 50 years with an underlying health condition): usual care alone; usual care plus azithromycin; and usual care plus doxycycline.[899] An interim analysis of the trial concluded that azithromycin and doxycycline offered no meaningful beneficial effect, in terms of time to recovery, hospitalization, or death compared with standard of care in patients ages 50 years and over who were treated at home in the early stages of infection.[897][900] Consult local drug formulary for information about contraindications, cautions, adverse effects, and drug interactions before prescribing these drugs.
Lopinavir/ritonavir
Lopinavir/ritonavir is an oral protease inhibitor. It is approved for the treatment of HIV infection, but is off-label for this indication. The World Health Organization strongly recommends against the use of lopinavir/ritonavir, regardless of disease severity. This recommendation is based on low- to moderate-certainty evidence.[722][764][765] The US National Institutes of Health guidelines panel recommends against the use of lopinavir/ritonavir except in the context of a clinical trial.[501] The Infectious Diseases Society of America also recommends against the use of lopinavir/ritonavir based on moderate-certainty evidence.[770] Evidence does not support the use of this drug. The WHO Solidarity trial found that lopinavir/ritonavir appears to have little or no effect on hospitalized patients, as indicated by overall mortality, initiation of ventilation, and duration of hospital stay.[837] The UK RECOVERY trial found that there is no beneficial effect of lopinavir/ritonavir in hospitalized patients, with no significant difference in 28-day mortality, risk of progression to mechanical ventilation or death, or duration of hospital stay between the two treatment arms (lopinavir/ritonavir versus usual care alone).[901] A systematic review and meta-analysis found that lopinavir/ritonavir had no significant advantage in efficacy over standard care, no antivirals, or other antiviral treatments.[902] Consult local drug formulary for information about contraindications, cautions, adverse effects, and drug interactions before prescribing this drug.
Hydroxychloroquine/chloroquine
Hydroxychloroquine and chloroquine are oral disease-modifying antirheumatic drugs with anti-inflammatory and immunomodulatory effects. These drugs have been shown to be effective against SARS-CoV-2 in vitro.[903][904] Hydroxychloroquine and chloroquine are already approved in some countries for certain conditions, but are off-label for this indication. The World Health Organization (WHO) strongly recommends against the use of hydroxychloroquine or chloroquine, regardless of disease severity, based on low- to moderate-certainty evidence.[722][764][765] The WHO also strongly recommends against the use of hydroxychloroquine for prevention of COVID-19. A systematic review and network meta-analysis found that hydroxychloroquine had a small or no effect on mortality and admission to hospital. There was a small or no effect on laboratory-confirmed infection, but probably increased adverse events leading to discontinuation.[905][906] The US National Institutes of Health guidelines panel recommends against the use of hydroxychloroquine or chloroquine in hospitalized patients.[501] The panel recommends against the use of both drugs in nonhospitalized patients, except in the context of a clinical trial. The panel recommends against the use of hydroxychloroquine for postexposure prophylaxis. The Infectious Diseases Society of America strongly recommends against the use of hydroxychloroquine or chloroquine in hospitalized patients based on moderate-certainty evidence.[770] Evidence does not support the use of these drugs for treatment. A Cochrane review found that hydroxychloroquine has no clinical benefit in hospitalized patients, with moderate‐ to high‐certainty evidence from several randomized trials, and a probable increase in adverse events associated with its use. Evidence for prevention of hospital admission in outpatients is very uncertain. Evidence for pre- or postexposure prophylaxis is limited.[907] A living systematic review concluded that there is low-strength evidence from trials and cohort studies that hydroxychloroquine has no positive effect on all-cause mortality or the need for mechanical ventilation. Trials show low strength of evidence for no positive effect on intubation or death and discharge from the hospital, whereas evidence from cohort studies about these outcomes remains insufficient. Data are insufficiently strong to support a treatment benefit of hydroxychloroquine for other outcomes (e.g., intensive care unit admission, symptom resolution). In trials where hydroxychloroquine is initiated in the outpatient setting, there is low strength of evidence that it reduces hospitalization; however, there is insufficient evidence from cohort studies.[908][909] The WHO Solidarity trial found that hydroxychloroquine appears to have little or no effect on hospitalized patients, as indicated by overall mortality, initiation of ventilation, and duration of hospital stay.[837] The UK RECOVERY trial found that hydroxychloroquine does not reduce the risk of death at 28 days compared with usual care.[910] A living systematic review and network meta-analysis found that hydroxychloroquine did not reduce the rate of infection, admission to hospital, or mortality compared with standard care or placebo when used for prophylaxis. More patients discontinued hydroxychloroquine because of adverse events.[862] Consult local drug formulary for information about contraindications, cautions, adverse effects, and drug interactions before prescribing these drugs.
Clinical trials
Various other treatments are in clinical trials around the world. Global coronavirus COVID-19 clinical trial tracker external link opens in a new window International trials to identify treatments that may be beneficial, such as the World Health Organization’s Solidarity trial, and the UK’s randomized evaluation of COVID-19 therapy (RECOVERY) trial, are ongoing. The RECOVERY Trial is currently testing these treatments: aspirin; baricitinib; dimethyl fumarate; and casirivimab/imdevimab. RECOVERY trial external link opens in a new window WHO: “Solidarity” clinical trial for COVID-19 treatments external link opens in a new window
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