Emerging treatments
Remdesivir
Remdesivir is a broad-spectrum antiviral agent that inhibits RNA-dependent RNA polymerase. It is approved in many countries, including the UK, US and Europe, for the treatment of COVID-19 in children ≥12 years of age (weighing ≥40 kg) and adults.[909][910] There are conflicting recommendations across international guidelines about the use of remdesivir. While UK and US guidelines recommend considering remdesivir in certain patients, the World Health Organization recommends against its use. It is important that you check your local guidance and protocols. The World Health Organization recommends against the use of remdesivir in hospitalized patients in addition to standard care, regardless of disease severity.[807][808][809] 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.[808][809] The UK National Institute for Health and Care Excellence recommends considering remdesivir for up to 5 days in adults and children ≥12 years of age and ≥40 kg who are in hospital and needing low-flow supplemental oxygen.[600] Do not use remdesivir in adults, young people, and children in hospital and on high-flow nasal oxygen, continuous positive airway pressure, noninvasive mechanical ventilation, or invasive mechanical ventilation, except as part of a clinical trial. There is limited evidence suggesting that remdesivir probably reduces the risk of death in hospitalized patients who need low-flow supplemental oxygen. However, evidence shows that remdesivir may increase the risk of death in people who are on high-flow nasal oxygen, continuous positive airway pressure, noninvasive ventilation, or invasive mechanical ventilation. Evidence does not suggest any greater benefit with a 10-day course of remdesivir compared with a 5-day course, but suggests an increased risk of harm. There may also be no benefit in completing the full course of remdesivir if the patient progresses to needing high-flow oxygen, noninvasive ventilation, or invasive mechanical ventilation during treatment. Evidence for remdesivir in children and young people is limited. The US National Institutes of Health guidelines panel recommends remdesivir in hospitalized adults who require supplemental oxygen.[568] 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.[857] 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. Evidence is conflicting. A 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.[862][863] 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.[911] The DisCoVeRy trial, a phase 3 randomized controlled open-label trial, found that no clinical benefit was observed (no significant difference in clinical status at days 15 and 29, time to hospital discharge, 28-day all-cause mortality) from the use of remdesivir plus standard of care in hospitalized patients, patients who were symptomatic for more than 7 days, and those who required oxygen support, compared with standard of care alone.[912] Consult local drug formulary for information about contraindications, cautions, adverse effects, and drug interactions before prescribing this drug. Acute kidney injury and renal impairment have been reported.
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 has been authorized for use in many countries, including the UK and the US, for the treatment and prophylaxis of COVID-19 in children ≥12 years of age (weighing ≥40 kg) and adults.[913][914][915] The European Medicines Agency has issued advice that casirivimab/imdevimab may be used for treatment in patients ≥12 years of age who do not require supplemental oxygen and who are at high risk of progressing to severe disease, and is currently evaluating an application for marketing authorization.[916] The World Health Organization recommends casirivimab/imdevimab for patients with nonsevere disease who are at highest risk of hospitalization, and patients with severe disease with a seronegative status.[807][808][809] Casirivimab/imdevimab probably reduces the risk of hospitalization and duration of symptoms in patients with nonsevere disease based on moderate-certainty evidence. While casirivimab/imdevimab achieves a substantial reduction in the relative risk of hospitalization, the absolute benefit will be trivial or unimportant in absolute terms for all but those who are at highest risk of disease (e.g., unvaccinated, older people, immunodeficiencies, and/or chronic disease). Casirivimab/imdevimab is also recommended in seronegative patients with severe or critical disease. It probably reduces mortality and possibly reduces the need for mechanical ventilation in patients who are seronegative based on moderate- and low-certainty evidence, respectively. Treatment is in addition to the current standard of care. The UK National Institute for Health and Care Excellence recommends casirivimab/imdevimab in hospitalized patients ≥12 years of age who have no detectable SARS-CoV-2 antibodies (seronegative), provided they meet all of the eligibility criteria and none of the exclusion criteria.[600] Patients are eligible for treatment if: infection is confirmed by molecular testing, or a multidisciplinary team has a high level of confidence in the diagnosis based on clinical and radiologic features; and patient is hospitalized specifically for the management of acute symptoms of COVID-19; and patient is negative for baseline serum anti-spike (anti-S) antibodies against SARS-CoV-2 (seronegative); and patient is either ≥50 years of age, or 12 to 49 years of age and immunocompromised. Do not offer casirivimab/imdevimab to people who have detectable SARS-CoV-2 antibodies (seropositive), or whose serostatus is unknown. Intravenous administration is recommended, and use is off-label in the UK for the dose recommended. The US National Institutes of Health guidelines panel recommends casirivimab/imdevimab for the treatment of nonhospitalized patients with mild to moderate disease who are at high risk of clinical progression, as defined by the emergency-use authorization criteria.[568] Treatment should be started as soon as possible after the patient receives a positive test result and within 10 days of symptom onset. Administration by intravenous infusion is recommended. However, if intravenous infusions are not feasible or would cause a delay in treatment, subcutaneous administration may be considered (note: doses differ between formulations). Use should be considered in patients with mild to moderate disease who are hospitalized for a reason other than COVID-19 if they otherwise meet the emergency-use authorization criteria for outpatient treatment. Not currently authorized for use in hospitalized patients with severe disease, but may be available through expanded access programs for patients who are hospitalized with severe disease who have not developed an antibody response or who are not expected to mount an effective immune response (e.g., immunocompromised patients). 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 US National Institutes of Health guidelines panel also recommends casirivimab/imdevimab for postexposure prophylaxis in people who are at high risk for progression to severe disease, provided they meet the following criteria: not fully vaccinated, or fully vaccinated but not expected to mount an adequate immune response; AND recent exposure to an infected individual that is consistent with the Centers for Disease Control and Prevention close contact criteria, or at high risk of exposure to an infected individual because of recent occurrence of infection in other individuals in the same institutional setting (e.g., nursing homes, prisons).[568] The Infectious Diseases Society of America suggests casirivimab/imdevimab for treatment 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 moderate-certainty evidence.[857] 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. The Infectious Diseases Society of America also suggests casirivimab/imdevimab for postexposure prophylaxis in people who are at high risk for progression to severe disease, based on low-certainty evidence.[857] Evidence supports the use of this treatment. A living systematic review and network meta-analysis found that casirivimab/imdevimab probably reduces the risk of hospitalization and reduces time to symptom resolution in patients with nonsevere disease, but is not different to standard of care for other outcomes (i.e., mortality, mechanical ventilation).[917] The original 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.[914] The UK RECOVERY trial found that among hospitalized patients who were seronegative at baseline, casirivimab/imdevimab significantly reduced the primary outcome of 28-day mortality by one fifth compared with usual care alone. There was clear evidence that the effect of treatment in seronegative patients differed from that in seropositive patients. Results are yet to be published.[918] Consult local drug formulary for information about contraindications, cautions, adverse effects, and drug interactions before prescribing this drug. Casirivimab/imdevimab may be given as an intravenous infusion or subcutaneously. 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 and etesevimab 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 authorized in many countries, including the US, for the treatment and prophylaxis of COVID-19 in children ≥12 years of age (weighing ≥40 kg) and adults who are at high risk for progressing to severe disease and/or hospitalization.[919][920] The European Medicines Agency has issued advice that bamlanivimab/etesevimab may be used in patients ≥12 years of age who do not require supplemental oxygen and who are at high risk of progressing to severe disease.[921] The US National Institutes of Health guidelines panel recommends bamlanivimab/etesevimab for the treatment of nonhospitalized patients with mild to moderate disease who are at high risk of clinical progression, as defined by the emergency-use authorization criteria.[568] Bamlanivimab/etesevimab is only recommended in regions where the combined frequency of potentially resistant variants (e.g., Beta, Gamma) is low. The Delta variant has demonstrated susceptibility to bamlanivimab/etesevimab in laboratory studies; therefore, bamlanivimab/etesevimab is recommended for the Delta variant. The US National Institutes of Health guidelines panel also recommends bamlanivimab/etesevimab for postexposure prophylaxis in people who are at high risk for progression to severe disease, provided they meet the following criteria: not fully vaccinated, or fully vaccinated but not expected to mount an adequate immune response; AND recent exposure to an infected individual that is consistent with the Centers for Disease Control and Prevention close contact criteria, or at high risk of exposure to an infected individual because of recent occurrence of infection in other individuals in the same institutional setting (e.g., nursing homes, prisons).[568] 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 moderate-certainty evidence.[857] 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. A living systematic review and network meta-analysis found that bamlanivimab/etesevimab may reduce the risk of hospitalization in patients with nonsevere disease, but is not different to standard of care for other outcomes (i.e., mortality, viral clearance, time to symptom resolution).[917] A randomized controlled trial in patients with mild to moderate disease found that 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.[922] A randomized controlled trial in high-risk ambulatory patients found that treatment with bamlanivimab/etesevimab reduced the risk of hospitalization and death compared with placebo and accelerated the reduction in viral load.[923] Consult local drug formulary for information about contraindications, cautions, adverse effects, and drug interactions before prescribing this drug. Bamlanivimab/etesevimab is given as an intravenous infusion. Circulating SARS-CoV-2 variants may be associated with resistance to monoclonal antibodies. Consult local guidance for details regarding specific variants and resistance.
Sotrovimab
Sotrovimab is an investigational monoclonal antibody with activity against SARS-CoV-2. It is designed to attach to the spike protein of the virus. Sotrovimab has been authorized for use in many countries, including the US, for the treatment of COVID-19 in children ≥12 years of age (weighing ≥40 kg) and adults who are at high risk for progressing to severe disease and/or hospitalization.[924] The European Medicines Agency has issued advice that sotrovimab may be used for treatment in patients ≥12 years of age who do not require supplemental oxygen and who are at high risk of progressing to severe disease.[925] The US National Institutes of Health guidelines panel recommends sotrovimab for the treatment of nonhospitalized patients with mild to moderate disease who are at high risk of clinical progression, as defined by the emergency-use authorization criteria.[568] Treatment should be started as soon as possible after the patient receives a positive test result and within 10 days of symptom onset. Use should be considered in patients with mild to moderate disease who are hospitalized for a reason other than COVID-19 if they otherwise meet the emergency-use authorization criteria for outpatient treatment. Not currently authorized for use in hospitalized patients with severe disease, but may be available through expanded access programs for patients who are hospitalized with severe disease who have not developed an antibody response or who are not expected to mount an effective immune response (e.g., immunocompromised patients). 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, monoclonal antibody products 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 sotrovimab 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 moderate-certainty evidence.[857] 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 sotrovimab. There are limited data on efficacy in high-risk patients between 12 and 18 years of age. Evidence is emerging. A living systematic review and network meta-analysis found that sotrovimab may reduce the risk of hospitalization in patients with nonsevere disease, but is not different to standard of care for other outcomes (i.e., mortality, mechanical ventilation).[917] Authorization was based on an interim analysis from a phase 1/2/3 randomized controlled trial in 583 nonhospitalized adults with mild to moderate disease that reported an 85% reduction in hospitalization or death compared with placebo.[924] Consult local drug formulary for information about contraindications, cautions, adverse effects, and drug interactions before prescribing this drug. Sotrovimab is given as an intravenous infusion. Circulating SARS-CoV-2 variants may be associated with resistance to monoclonal antibodies. Consult local guidance for details regarding specific variants and resistance.
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; the agency is currently evaluating an application for marketing authorization for this indication.[926][927] Evidence is limited. According to press releases from the manufacturer, regdanivimab reduced progression from mild-moderate to severe disease by 50%, and from moderate to severe disease by 68%, and reduced the risk of hospitalization or death by 72% in patients at high risk of progressing to severe disease. However, results from the phase 2/3 trials are yet to be published.[928][929] Regdanivimab has also demonstrated neutralizing capability against key emerging mutations, including the Alpha variant.[930]
Janus kinase inhibitors
Janus kinase inhibitors are thought to prevent the dysregulated production of proinflammatory cytokines in patients with severe or critical disease. Drugs within this class include baricitinib, tofacitinib, fedratinib, and ruxolitinib. Baricitinib has been granted an emergency-use authorization in the US 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 (with or without remdesivir).[931] 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.[932] Other Janus kinase inhibitors are not authorized for use in patients with COVID-19 as yet. The US National Institutes of Health guidelines panel recommends baricitinib, in combination with dexamethasone alone or dexamethasone plus remdesivir, in recently hospitalized patients on high-flow oxygen or noninvasive ventilation with rapidly increasing oxygen needs and systemic inflammation.[568] The panel recommends against the use of baricitinib in combination with tocilizumab except in the context of a clinical trial. There is potential for an additive risk of infection. There is insufficient evidence to recommend either for or against the use of baricitinib in children. The panel recommends tofacitinib may be used as an alternative if baricitinib is not available or it is not feasible to use it. The Infectious Diseases Society of America suggests baricitinib in hospitalized adults with severe disease who have elevated inflammatory markers, but who are not on invasive mechanical ventilation. The panel suggests tofacitinib in hospitalized adults with severe disease who are not on noninvasive or invasive mechanical ventilation.[857] Baricitinib is recommended for up to 14 days or until discharge from hospital. It appears to demonstrate the most benefit in those on high-flow oxygen or noninvasive ventilation at baseline. The guideline panel suggests baricitinib with remdesivir, rather than remdesivr alone, in patients who cannot receive a corticosteroid because of a contraindication. Tofacitinib appears to demonstrate the most benefit in those on supplemental or high-flow oxygen. Patients treated with tofacitinib should be on at least prophylactic-dose anticoagulation. Patients who receive baricitinib or tofacitinib should not receive an interleukin-6 inhibitor. Evidence is emerging. Emergency-use authorization of baricitinib 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.[933] 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.[862][863] Another systematic review and network meta-analysis found that Janus kinase inhibitors are also associated with a reduced risk of mortality, and clinical improvement in hospitalized patients.[934] A meta-analysis that included six cohort studies and five clinical trials involving over 2000 participants treated with either baricitinib or ruxolitinib found that use of Janus kinase inhibitors reduced the need for invasive mechanical ventilation and increased survival, but did not reduce the length of hospitalization. The evidence was most convincing for baricitinib. Timing of treatment may be important in determining the impact on outcomes.[935] A meta-analysis that included four randomized controlled trials and 1300 participants found that treatment with a Janus kinase inhibitor in addition to standard of care reduced the risk of death by 43%, and mechanical ventilation or ECMO by 36% compared with control.[936] Consult local drug formulary for information about contraindications, cautions, adverse effects, and drug interactions before prescribing this drug. The US Food and Drug Administration has issued a warning about increased risk of serious heart-related events, cancer, blood clots, and death with certain JAK inhibitors.[937]
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.[938] 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.[939] The US National Institutes of Health guidelines panel recommends against the use of low-titer convalescent plasma.[568] 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.[857] 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. A living systematic review and network meta-analysis found that convalescent plasma may not confer any meaningful benefit in patients with any disease severity. Whether or not high-titer convalescent plasma confers any benefit remains uncertain.[917] A Cochrane review found high-certainty evidence that convalescent plasma does not reduce mortality and has little to no impact on measures of clinical improvement for the treatment of moderate to severe disease.[940] Evidence from meta-analyses is conflicting. While some meta-analyses 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, others have found a reduction in mortality, especially when trials with low-titer convalescent plasma were removed from the analyses.[941][942][943][944][945] The UK RECOVERY trial found that high-titer convalescent plasma did not improve 28-day mortality or other prespecified outcomes (hospital discharge within 28 days, progression to invasive mechanical ventilation) in hospitalized patients compared with usual care.[946] 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.[947]
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 states that there are insufficient data to recommend either for or against the use of anti-SARS-CoV-2 specific immune globulin.[568] Evidence is limited. A living systematic review and network meta-analysis found that IVIG may not confer any meaningful benefit in patients with any disease severity.[917] A meta-analysis of four clinical trials and three cohort studies with 825 hospitalized patients found that IVIG reduced mortality in patients with critical disease; however, there was no significant difference between the severe and nonsevere subgroups.[948] 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.[949] Ivermectin is already approved in some countries for parasitic infections, but is off-label for this indication. The World Health Organization does not recommend ivermectin except in the context of a clinical trial.[807] 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.[808][809] 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.[568] The Infectious Diseases Society of America suggests against the use of ivermectin in outpatients and hospitalized patients outside of the context of a clinical trial.[857] Evidence is emerging. A meta-analysis of 24 randomized controlled trials with 3400 participants found moderate-certainty evidence that ivermectin provided a significant survival benefit when used for treatment. Low-certainty evidence supports a likely clinical benefit in terms of improvement and deterioration. Low-certainty evidence also suggests a significant effect in prophylaxis. Overall, the evidence suggested that early use may reduce morbidity and mortality.[950] A meta-analysis of 18 randomized controlled trials found statistically significant reductions in mortality, time to clinical recovery, and time to viral clearance with use of ivermectin.[951] A meta-analysis of nine randomized controlled trials found that ivermectin was associated with decreased mortality compared with standard of care or placebo, with a low certainty of evidence.[952] Another 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.[953] 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.[954] 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.[955] One meta-analysis of 10 randomized controlled trials found that ivermectin did not reduce all-cause mortality, length of hospital stay, or respiratory viral clearance in patients with mild to moderate disease.[956] The PRINCIPLE trial in the UK is currently investigating the use of ivermectin.[957] Consult local drug formulary for information about contraindications, cautions, adverse effects, and drug interactions before prescribing this drug.
Molnupiravir
An experimental oral antiviral drug that is metabolized into a ribonucleoside analog that resembles cytidine. The manufacturer has submitted an emergency-use authorization application to the US Food and Drug Administration for the treatment of mild to moderate disease in at-risk adults. If authorized, it will be the first oral antiviral medication available for COVID-19. Evidence is limited. According to a press release from the manufacturer, molnupiravir significantly reduced the risk of hospitalization or death in at-risk, nonhospitalized adults with mild to moderate disease in a planned interim analysis of the phase 3 MOVe-OUT trial (775 patients). Molnupiravir reduced the risk of hospitalization or death by approximately 50% (absolute risk reduced from 14% to 7%), with efficacy unaffected by the timing of symptom onset, underlying risk factors, or SARS-CoV-2 variant type. Recruitment into the study is being stopped early due to these positive results.[958][959]
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 European Medicines Agency has started to evaluate an application to extend the use of anakinra to include the treatment of COVID-19 in adults with pneumonia who are at risk of developing severe respiratory failure.[960] 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.[568] 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.[961] Evidence is limited. A systematic review and meta-analysis of nine studies (eight observational studies and one randomized controlled trial) found that anakinra significantly reduced mortality in hospitalized patients with moderate to severe disease. Subgroup analysis identified patients with C-reactive protein levels >100 mg/L may benefit most.[962] A systematic review and meta-analysis of nine observational studies found that anakinra reduced the need for invasive mechanical ventilation and mortality risk in hospitalized nonintubated patients compared with standard of care.[963] A systematic review and meta-analysis of 15 studies (five observational studies, five case series, four case reports, and one randomized controlled trial) also found that anakinra significantly reduced the need for invasive mechanical ventilation and mortality risk compared with standard care alone.[964] Consult local drug formulary for information about contraindications, cautions, adverse effects, and drug interactions before prescribing this drug.
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.[965] Colchicine is already approved in some countries for indications such as gout and familial Mediterranean fever, but is off-label for this indication. The UK National Institute for Health and Care Excellence does not recommend colchicine in hospitalized patients.[600] The guideline also recommends against its use in community settings. 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.[568] The panel recommends against its use in hospitalized patients. 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.[966] Evidence is limited. 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.[862][863] 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.[967] Another systematic review and meta-analysis supports the reduction in mortality; however, meta-regression analysis found that the benefit was reduced as age increased.[968] A double-blind, placebo-controlled, randomized trial of over 4400 nonhospitalized patients found that colchicine led to a lower rate of the composite of death or hospital admission compared with placebo among patients with polymerase chain reaction (PCR)-confirmed disease; however, the effect was not statistically significant when participants without a PCR-confirmed diagnosis were included.[969] 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.[970] Studies are inconclusive in patients with mild to moderate disease, and adverse effects are significant.[971] 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.[972] 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.[568] Evidence is limited. A systematic review and meta-analysis found that mesenchymal stem cell therapy significantly reduced the incidence of adverse events and mortality.[973] 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.[974]
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.[568] 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.[911] 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.[975] 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.[976][977] 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.[978][979][980][981] 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.[568] 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.[982] Evidence is limited. A Cochrane review found there is currently insufficient evidence to determine the benefits and harms of vitamin D supplementation. The evidence is very uncertain. There was substantial clinical and methodological heterogeneity of included studies, mainly due to different supplementation strategies, formulations, vitamin D status of participants, and reported outcomes.[983] Meta-analyses found that vitamin D might be associated with improved clinical outcomes and that there may be a potential role for vitamin D supplementation in reducing disease severity, but noted that additional evidence is required.[984][985] The evidence is currently insufficient to support the routine use of vitamin D as its effectiveness appears to depend on the dose used, baseline vitamin D levels, and the severity of disease.[986] 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.[987]
Vitamin C
Vitamin C supplementation has shown promise in the treatment of viral infections.[988] High-dose intravenous vitamin C is being trialed in some centers for the treatment of severe disease.[989] 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.[568] 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.[990]
Fluvoxamine
Fluvoxamine is a selective serotonin-reuptake inhibitor that has anti-inflammatory effects.[991] Fluvoxamine is already approved in some countries for indications such as depression and obsessive compulsive disorder, 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 fluvoxamine.[568] Evidence is limited. A preliminary double-blind, randomized controlled trial found that adult outpatients had a lower likelihood of clinical deterioration over 15 days compared with placebo; however, the study was limited by a small sample size and short follow-up duration.[992] A prospective cohort study in the setting of a mass outbreak found that fluvoxamine may prevent clinical deterioration requiring hospitalization and symptoms persisting beyond 2 weeks.[993] Consult local drug formulary for information about contraindications, cautions, adverse effects, and drug interactions before prescribing this drug.
Nitazoxanide
Nitazoxanide is a broad-spectrum antiparasitic agent with in vitro activity against SARS-CoV-2 that is already approved in some countries for indications such as cryptosporidiosis and giardiasis, but is off-label for this indication. The US National Institutes of Health guidelines panel recommends against the use of nitazoxanide except in the context of a clinical trial.[568] Evidence is limited. A randomized, double-blind pilot trial found an evident decrease in the time for hospital discharge, faster evolution to reverse transcription polymerase chain reaction negativity, and a higher reduction of inflammatory markers among patients treated with nitazoxanide compared with placebo. However, this was a small, proof-of-concept trial.[994] A multicenter, randomized, double-blind, placebo-controlled trial in adults with mild disease found that nitazoxanide was associated with reduced viral load but not reduced time to symptom resolution.[995] Consult local drug formulary for information about contraindications, cautions, adverse effects, and drug interactions before prescribing this drug.
Granulocyte-macrophage colony-stimulating factor (GM-CSF) inhibitors
GM-CSF inhibitors (e.g., lenzilumab, mavrilimumab, otilimab) may mitigate lung inflammation in severe and critical disease by minimizing downstream production of numerous pro-inflammatory mediators involved in the pathogenesis of disease. These agents are currently investigational. The US Food and Drug Administration has declined an emergency-use authorization for lenzilumab to treat hospitalized COVID-19 patients as it was unable to conclude that the known and potential benefits of lenzilumab outweigh the known and potential risks of its use.[996] The UK Medicines and Healthcare products Regulatory Agency is currently reviewing an application for a conditional marketing authorization for lenzilumab. The US National Institutes of Health guidelines panel states that there is currently insufficient evidence to recommend either for or against the use of GM-CSF inhibitors.[568] Evidence is limited. A meta-analysis found that GM-CSF inhibitors were associated with a 23% reduction in the risk of mortality, but increased the risk of intensive care unit admission.[997] A small multicenter, double-blind, randomized, placebo-controlled trial found that there was no significant difference in the proportion of patients with severe disease, hypoxemia, and systemic hyperinflammation who were free of supplemental oxygen at day 14 after treatment with mavrilimumab compared with placebo.[998]
Inhaled corticosteroids
Inhaled budesonide is undergoing clinical trials and shows promise.[999] It is already approved in some countries for indications such as asthma and COPD, but is off-label for this indication. The UK Medicines and Healthcare products Regulatory Agency states that inhaled budesonide can be considered on a case-by-case basis in eligible patients who meet all of the following criteria (and who do not meet specific exclusion criteria): patients with onset of symptoms within the past 14 days, and symptoms are ongoing; confirmation of diagnosis by molecular testing within the past 14 days; age 65 years and over, or age 50 to 64 years with a comorbidity consistent with a long-term health condition.[1000] The European Medicines Agency advises that there is currently insufficient evidence that inhaled corticosteroids are beneficial.[1001] The US National Institutes of Health guidelines panel states that there is currently insufficient evidence to recommend either for or against the use of inhaled budesonide.[568] Evidence is limited. The PRINCIPLE trial has reported a 3-day median benefit in self-reported recovery for patients in the community setting who are at higher risk of complications and who received inhaled budesonide.[1002] The impact on hospitalization rates or mortality has not been established. Consult local drug formulary for information about contraindications, cautions, adverse effects, and drug interactions before prescribing this drug.
Antibiotics
Azithromycin is a macrolide antibiotic, and doxycycline is a tetracycline antibiotic. Both are approved for use in various bacterial infections. The UK National Institute for Health and Care Excellence does not recommend the use of azithromycin or doxycycline.[600] The guideline panel considered that the results from studies of azithromycin for moderate to critical disease in the hospital setting and mild to moderate disease in the community setting showed no meaningful benefit in any of the critical outcomes. 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.[1003] 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.[568] Evidence does not support the use of these drugs. A systematic review and meta-analysis found that azithromycin was not associated with an improvement in hospitalization rate, intensive care unit admission, need for respiratory support, or mortality rate compared with control.[1004] The overall quality of evidence was low to very low. 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.[1005] The UK PRINCIPLE trial found that doxycycline use was not associated with clinically meaningful reductions in time to recovery or hospital admissions or deaths in patients with suspected disease in the community who were at high risk of adverse outcomes.[1006] The ATOMIC2 open-label randomized trial found that adding azithromycin to standard of care treatment in nonhospitalized patients with mild to moderate disease did not reduce the risk of subsequent hospital admission or death.[1007] 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.[1003][1008] 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.[807][808][809] The US National Institutes of Health guidelines panel recommends against the use of lopinavir/ritonavir except in the context of a clinical trial.[568] The Infectious Diseases Society of America also recommends against the use of lopinavir/ritonavir based on moderate-certainty evidence.[857] 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.[911] 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).[1009] 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.[1010] 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.[1011][1012] 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.[807][808][809] 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.[1013][1014] The US National Institutes of Health guidelines panel recommends the use of hydroxychloroquine or chloroquine (with or without azithromycin) in hospitalised or nonhospitalized patients.[568] The panel also 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.[857] The guideline also recommends against the use of hydroxychloroquine for postexposure prophylaxis. 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.[1015] 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.[1016][1017] 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.[911] The UK RECOVERY trial found that hydroxychloroquine does not reduce the risk of death at 28 days compared with usual care.[1018] 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.[955] 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. RECOVERY trial external link opens in a new window WHO: COVID-19 “Solidarity” therapeutics trial external link opens in a new window
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