Emerging treatments

Nirmatrelvir/ritonavir

Nirmatrelvir is an experimental oral severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-3CL protease inhibitor antiviral drug. Coadministration with a low dose of ritonavir (which is commonly administered with other protease inhibitors as part of antiretroviral therapy for HIV infection) helps to slow the hepatic metabolism of nirmatrelvir so it remains active in the body for a longer period of time.

The World Health Organization strongly recommends nirmatrelvir/ritonavir in adults with non-severe disease who are at highest risk of hospitalisation (e.g., older age, immunosuppression and/or chronic diseases, unvaccinated for COVID-19). It recommends against the use of nirmatrelvir/ritonavir in patients with non-severe disease who are at low risk of hospitalisation.[21][787][788]

  • Nirmatrelvir/ritonavir should be initiated as soon as possible after diagnosis, ideally within 5 days of symptom onset. The treatment course is 5 days.

  • It is not recommended in pregnant and breastfeeding women or children. A dose reduction is required in patients with renal impairment.

  • Nirmatrelvir/ritonavir likely reduces hospital admission in patients with non-severe disease (moderate-certainty evidence), and may have little or no impact on mortality (low-certainty evidence).

  • Treatment does not increase the likelihood of adverse effects leading to drug discontinuation (high-certainty evidence). However, diarrhoea and dysgeusia occur more frequently with nirmatrelvir/ritonavir compared with placebo.

  • Nirmatrelvir/ritonavir is a superior choice to other treatments for non-severe disease because it may have greater efficacy in preventing hospitalisation compared with the alternatives, has fewer concerns with respect to harms than does molnupiravir, and is easier to administer than intravenous remdesivir and the monoclonal antibodies.

The UK National Institute for Health and Care Excellence recommends considering nirmatrelvir/ritonavir in adults ≥18 years of age who do not need supplemental oxygen, and are within 5 days of symptom onset, and are thought to be at high risk of progression to severe disease.[20]

The US National Institutes of Health guidelines panel recommends nirmatrelvir/ritonavir in non-hospitalised patients ≥12 years of age (weighing ≥40 kg) and adults with mild to moderate disease who are at high risk of disease progression.[19]

  • If a patient requires hospitalisation after starting treatment, the full treatment course can be completed at the healthcare provider’s discretion.

  • The Infectious Diseases Society of America also recommends the use of nirmatrelvir/ritonavir in these patients.[510]

Evidence is emerging.

  • Evidence of clinical efficacy is based on an interim analysis of data from a single placebo-controlled trial in unvaccinated adults that was conducted before the emergence of the Omicron variant.

  • Nirmatrelvir/ritonavir was found to reduce the risk of hospitalisation or death by 89% (within 3 days of symptom onset) and 88% (within 5 days of symptom onset) compared with placebo in non-hospitalised high-risk adults in the phase 2/3 EPIC-HR randomised double-blind clinical trial.[1008]

  • Nirmatrelvir/ritonavir appears to retain activity against the Omicron variant and other variants of concern in vitro.[1009]

Consult local drug formulary for information about contraindications, cautions, adverse effects, and drug interactions before prescribing this drug. Ritonavir-boosted nirmatrelvir has significant and complex drug-drug interactions, primarily due to the ritonavir component of the combination. Carefully review the patient’s medication history before starting treatment.

In the UK, report any pregnancies that occur during use of this drug, including paternal use, to the UK COVID-19 Antivirals Pregnancy Registry.

Molnupiravir

A prodrug that is metabolised to the ribonucleoside analogue N-hydroxycytidine (NHC), which distributes into cells where it is phosphorylated to form the pharmacologically active ribonucleoside triphosphate (NHC-TP). NHC-TP is incorporated into viral RNA by the viral RNA polymerase, resulting in an accumulation of errors in the viral genome leading to inhibition of replication.

The World Health Organization conditionally recommends molnupiravir in adults with non-severe disease who are at highest risk of hospitalisation (e.g., older age, immunosuppression and/or chronic diseases, unvaccinated for COVID-19).[21][787][788]

  • Molnupiravir should be initiated as soon as possible after diagnosis, ideally within 5 days of symptom onset. The treatment course is 5 days.

  • It is not recommended in pregnant and breastfeeding women, or children. Animal studies have shown reproductive toxicity, and it may affect bone and cartilage growth. A pregnancy test should be performed prior to initiation of treatment. Contraception is recommended during treatment and for 4 days after the last dose in women of childbearing potential, and for at least 3 months after the last dose in men of reproductive potential who are sexually active with women of childbearing potential.

  • Longer-term harms (e.g., genotoxicity, resistance) remain unknown in the absence of clinical evidence, both for individual patients and at the population level. The World Health Organization recommends active monitoring for drug safety, along with other strategies to mitigate potential harms as this is a new drug with very little safety data.

  • Molnupiravir probably reduces hospital admission and time to symptom resolution (moderate-certainty evidence), and may reduce mortality (low-certainty evidence), but effect on mechanical ventilation is very uncertain (very low-certainty evidence).

  • The conditional recommendation reflects the concern for widespread treatment with molnupiravir before more safety data become available.

The UK National Institute for Health and Care Excellence recommends considering molnupiravir in adults ≥18 years of age who do not need supplemental oxygen, and are within 5 days of symptom onset, and are thought to be at high risk of progression to severe disease.[20]

The US National Institutes of Health guidelines panel recommends molnupiravir in non-hospitalised adults ≥18 years of age with mild to moderate disease who are at high risk of disease progression, only when preferred therapies are not available, feasible to use, or clinically appropriate.[19]

  • If a patient requires hospitalisation after starting treatment, the full treatment course can be completed at the healthcare provider’s discretion.

  • The Infectious Diseases Society of America also recommends the use of molnupiravir in these patients.[510]

Evidence is emerging.

  • Evidence of clinical efficacy is based on an interim analysis of data from a single placebo-controlled trial in unvaccinated adults that was conducted before the emergence of the Omicron variant.

  • According to a press release from the manufacturer, molnupiravir significantly reduced the risk of hospitalisation or death in the 29 days after use in at-risk, non-hospitalised, unvaccinated adults with mild to moderate disease in an analysis of the phase 3 MOVe-OUT trial (1433 patients). Molnupiravir reduced the relative risk of hospitalisation or death by approximately 30% (absolute risk reduced from 9.7% to 6.8%).[1010] This figure is less than the manufacturer’s original press release, which stated use of molnupiravir resulted in a 50% relative risk reduction based on an early interim analysis. Recruitment into the study was stopped early due to these positive results. However, the trial was underpowered to detect clinically important adverse effects and did not include children or pregnant women, and the trial population was unvaccinated and recruited before the most recent variants emerged. Final trial results are yet to be peer reviewed and published, but an interim analysis of earlier data has been published.[1011] Results from the phase 2 portion of the study have also been published.[1012]

  • Two phase 1 double-blind, randomised, placebo-controlled trials showed that molnupiravir was safe and tolerable without any serious adverse effects. A phase 2 study found that molnupiravir significantly lowered time to viral clearance in patients with mild to moderate disease compared with placebo. However, it was not effective in moderate to severe disease. Several phase 3 trials are ongoing. There are no data evaluating the role of molnupiravir in breakthrough infections following vaccination.[1013]

  • Molnupiravir appears to retain activity against the Omicron variant and other variants of concern in vitro.[1009]

Consult local drug formulary for information about contraindications, cautions, adverse effects, and drug interactions before prescribing this drug.

In the UK, report any pregnancies that occur during use of this drug, including paternal use, to the UK COVID-19 Antivirals Pregnancy Registry.

Anakinra

Anakinra is an intravenous/subcutaneous interleukin-1 inhibitor. It is being trialled 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 approved anakinra in adults with pneumonia who require low- or high-flow supplemental oxygen and who are at risk of developing severe respiratory failure, as determined by blood soluble urokinase plasminogen activator receptor (suPAR) levels of at least 6 nanograms/mL.[1014]

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 haemophagocytic lymphohistiocytosis triggered by SARS-CoV-2 or a similar coronavirus.[1015]

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.[19]

Evidence is emerging.

  • A Cochrane review did not find evidence for an important beneficial effect of interleukin-1 inhibitors. The evidence is uncertain or very uncertain for several outcomes. Anakinra probably results in little or no improvement in symptoms at 28 days after treatment. It is uncertain whether anakinra makes a difference to the number of deaths at 28 days after treatment.[1016]

  • A systematic review and meta-analysis of nine studies (eight observational studies and one randomised controlled trial) found that anakinra significantly reduced mortality in hospitalised patients with moderate to severe disease. Subgroup analysis identified patients with C-reactive protein levels >100 mg/L may benefit most.[1017]

  • A systematic review and meta-analysis of nine observational studies found that anakinra reduced the need for invasive mechanical ventilation and mortality risk in hospitalised non-intubated patients compared with standard of care.[1018]

  • A systematic review and meta-analysis of 15 studies (five observational studies, five case series, four case reports, and one randomised controlled trial) also found that anakinra significantly reduced the need for invasive mechanical ventilation and mortality risk compared with standard care alone.[1019]

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.[1020] 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 the use of colchicine.[20]

  • Evidence in hospitalised patients and community settings found no benefit of effect on hospitalisation, recovery time, all-cause mortality, mechanical ventilation, clinical progression, intensive care unit admission, or hospital discharge within 28 days.

The US National Institutes of Health guidelines panel recommends against the use of colchicine for the treatment of hospitalised patients, and against its use in non-hospitalised patients except in the context of a clinical trial.[19]

Evidence does not currently support the use of this treatment.

  • A Cochrane review found that the use of colchicine probably has little to no influence on mortality or clinical progression in hospitalised patients with moderate to severe disease, compared with placebo or standard care alone (moderate-certainty evidence). Evidence for effect on all-cause mortality for people with asymptomatic or mild disease is uncertain; however, use probably results in a slight reduction in hospital admissions or 28-day mortality.[1021]

  • A living systematic review and network meta-analysis found that colchicine may reduce mortality (low-certainty evidence) and probably reduces the duration of hospitalisation (low-certainty evidence) compared with standard care.[839][840]

  • The largest meta-analysis to date (approximately 16,000 patients), which included six randomised controlled trials, found that colchicine did not significantly reduce mortality, need for ventilatory support, intensive care unit admission, or length of hospital stay compared with supportive care only, and patients taking colchicine had a higher risk of adverse events. The GRADE quality of evidence was moderate for most outcomes.[1022]

  • The UK PRINCIPLE trial found that colchicine did not improve time to recovery in people in the community at higher risk of complications compared with usual care alone. There was also no evidence for a benefit in hospitalisations or deaths; however, estimates were imprecise due to the few hospitalisations in the trial.[1023]

  • The UK RECOVERY trial found that colchicine was not associated with reductions in 28-day mortality, duration of hospital stay, or risk of progressing to invasive mechanical ventilation or death in hospitalised adults.[1024]

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 minimising 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 authorisation for lenzilumab to treat hospitalised 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.[1025] The UK Medicines and Healthcare products Regulatory Agency is currently reviewing an application for a conditional marketing authorisation 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.[19]

Evidence is emerging.

  • A phase 3, randomised, double-blind, placebo-controlled trial found that lenzilumab significantly improved survival without invasive mechanical ventilation to day 28 in hospitalised patients.[1026]

  • A small multicentre, double-blind, randomised, placebo-controlled trial found that there was no significant difference in the proportion of patients with severe disease, hypoxaemia, and systemic hyperinflammation who were free of supplemental oxygen at day 14 after treatment with mavrilimumab compared with placebo.[1027]

Convalescent plasma

Convalescent plasma is a blood product that contains antibodies to SARS-CoV-2 from patients who have recovered. High-titre convalescent plasma (i.e., plasma with high SARS-CoV-2 antibody titres) has been granted an emergency-use authorisation in the US for the treatment of hospitalised patients early in the disease course, and to those hospitalised patients who have impaired humoral immunity and cannot produce an adequate antibody response. Low-titre convalescent plasma is no longer authorised.[1028] It has not been authorised for this indication in the UK or Europe.

The World Health Organization recommends against the use of convalescent plasma.[21][787][788]

  • The guideline recommends against using convalescent plasma in patients with non-severe disease. In these patients, convalescent plasma did not result in an important impact on mortality, based on high-certainty evidence. Convalescent plasma probably did not impact mechanical ventilation, based on moderate-certainty evidence. There were no data evaluating the risk of hospitalisation and therefore the impact is very uncertain.

  • The guideline recommends against using convalescent plasma in patients with severe or critical disease, except in the context of a clinical trial. In these patients, convalescent plasma may not result in an important impact on mortality, mechanical ventilation, time to symptom improvement, length of hospital stay, or ventilator-free days, based on low-certainty evidence.

UK guidance recommends that convalescent plasma should not be used in the management of hospitalised patients with suspected or confirmed infection.[1029]

The US National Institutes of Health guidelines panel recommends against the use of convalescent plasma in immunocompetent hospitalised patients.[19]

  • The panel recommends against the use of convalescent plasma collected prior to the emergence of the Omicron variant.

  • There is insufficient evidence to recommend either for or against the use of high-titre convalescent plasma collected after the emergence of the Omicron variant for the treatment of immunocompromised patients and non-hospitalised immunocompetent patients.

  • Use in hospitalised children with impaired immunity may be considered on a case-by-case basis provided that they meet the emergency-use authorisation criteria.

The Infectious Diseases Society of America recommends against the use of convalescent plasma in hospitalised patients, based on moderate-certainty evidence.[510]

  • The guideline panel suggests US Food and Drug Administration-qualified high-titre convalescent plasma for ambulatory patients with mild to moderate disease who are at high risk for progression to severe disease if they have no other treatment options, and within 8 days of symptom onset, based on low-certainty evidence.

Evidence does not currently support the use of this treatment.

  • 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-titre convalescent plasma confers any benefit remains uncertain.[1030]

  • 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.[1031]

  • 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-titre convalescent plasma were removed from the analyses.[1032][1033][1034][1035][1036][1037] A prospective individual patient data meta-analysis of international randomised controlled trials collaborating in the COMPILE study in hospitalised, non-critically ill patients found that convalescent plasma was associated with neither benefit nor harm consistently across trials.[1038]

  • The UK RECOVERY trial found that high-titre convalescent plasma did not improve 28-day mortality or other prespecified outcomes (hospital discharge within 28 days, progression to invasive mechanical ventilation) in hospitalised patients compared with usual care.[1039]

  • A randomised controlled trial found that administration of convalescent plasma to symptomatic adult outpatients (regardless of risk factors for disease progression or vaccination status) within 9 days of symptom onset reduced the risk of disease progression leading to hospitalisation.[1040]

  • Patient factors may help identify which patients would benefit most from treatment with convalescent plasma. Patients with comorbidities (diabetes, cardiovascular and pulmonary diseases), with blood type A or AB, and at an early disease stage may benefit most, while those without pre-existing conditions and at more advanced stages of disease could potentially be harmed.[1041]

Intravenous immunoglobulin

Intravenous immunoglobulin (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 immunoglobulin.[19]

Evidence does not currently support the use of this treatment.

  • A living systematic review and network meta-analysis found that IVIG may not confer any meaningful benefit in patients with any disease severity.[1030]

  • A meta-analysis of four clinical trials and three cohort studies with 825 hospitalised patients found that IVIG reduced mortality in patients with critical disease; however, there was no significant difference between the severe and non-severe subgroups.[1042]

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 pathological changes that occur in the lungs, and inhibit the cell-mediated immune inflammatory response.[1043] 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.[19]

Evidence is emerging.

  • Systematic reviews and meta-analyses have found that mesenchymal stem cell therapy may reduce the incidence of adverse events and mortality; however, evidence is limited and further research is required.[1044][1045][1046]

  • 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 enrolment, although the trial will be completed with the patients currently enrolled, with follow-up as planned.[1047]

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 hospitalised patients except in the context of a clinical trial.[19]

  • The panel recommends against the use of interferon beta for the treatment of hospitalised patients.

  • The panel recommends against the use of interferon alfa or lambda for the treatment of hospitalised patients, except in the context of a clinical trial.

  • The panel recommends against the use of interferon for the treatment of non-hospitalised patients with mild to moderate disease, except in the context of a clinical trial.

Evidence does not currently support the use of this treatment.

  • The WHO Solidarity trial found that interferon beta-1a appears to have little or no effect on hospitalised patients, as indicated by overall mortality, initiation of ventilation, and duration of hospital stay.[833]

  • A randomised, placebo-controlled, phase 2 trial found that nebulised interferon beta-1a was associated with a higher odds of clinical improvement and more rapid recovery.[1048]

  • 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.[1049][1050]

Consult local drug formulary for information about contraindications, cautions, adverse effects, and drug interactions before prescribing these drugs.

Ivermectin

Ivermectin is a broad-spectrum antiparasitic agent. It has been shown to be effective against SARS-CoV-2 in vitro.[1051] 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.[21]

  • 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.[787][788] For most key outcomes, including mortality, mechanical ventilation, hospital admission, duration of hospitalisation, and viral clearance, the evidence is of very low certainty.

The UK National Institute for Health and Care Excellence does not recommend ivermectin except as part of a clinical trial.[20]

The US National Institutes of Health guidelines panel recommends against the use of ivermectin, except in the context of a clinical trial .[19]

  • The Infectious Diseases Society of America suggest against the use of ivermectin in outpatients and hospitalised patients outside of the context of a clinical trial.[510]

Evidence is emerging.

  • A Cochrane review found no evidence to support the use of ivermectin for treating or preventing infection, but the evidence base was limited (as of 26 May 2021). The safety and efficacy of ivermectin was uncertain based on very low- to low-certainty evidence. Overall, the reliable evidence available does not support the use of ivermectin for treatment or prevention outside of well‐designed randomised trials.[1052]

  • Data from meta-analyses are conflicting. A meta-analysis of 24 randomised 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.[1053] Other meta-analyses also support an improvement in clinical outcomes with use of ivermectin, although the quality of evidence is very low to low.[1054][1055][1056][1057][1058] However, there are other meta-analyses that found that ivermectin did not reduce all-cause mortality, length of hospital stay, incidence of mechanical ventilation, time to clinical recovery, or respiratory viral clearance.[1058][1059][1060]

  • One meta-analysis found that strongyloidiasis prevalence interacts with the relative risk of mortality in ivermectin trials for the outcome of mortality, and no evidence was found to suggest that ivermectin had any role in preventing mortality in patients with COVID-19 in regions where strongyloidiasis was not endemic.[1061]

  • One meta-analysis found that ivermectin was effective when used for pre-exposure prophylaxis in preventing transmission among healthcare workers in low- and middle-income countries; however, evidence was limited.[1062]

  • The PRINCIPLE trial in the UK is currently investigating the use of ivermectin.[1063]

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.[19]

Evidence is emerging.

  • A randomised, double-blind, placebo-controlled trial found that nitazoxanide may reduce the risk of progression to severe disease in outpatients with mild to moderate disease who are at high risk of disease progression, and reduce the time to sustained clinical recovery in patients with mild disease.[1064]

  • A randomised 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.[1065]

  • A multicentre, randomised, 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.[1066]

Consult local drug formulary for information about contraindications, cautions, adverse effects, and drug interactions before prescribing this drug.

Fluvoxamine

Fluvoxamine is a selective serotonin-reuptake inhibitor that has anti-inflammatory and possible antiviral effects.[1067] 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.[19]

  • The Infectious Diseases Society of America recommends fluvoxamine in ambulatory patients only in the context of a clinical trial.[510]

Evidence is emerging.

  • A meta-analysis of randomised controlled trials, including the TOGETHER trial (a randomised placebo-controlled trial with nearly 1500 participants), found that patients receiving fluvoxamine were less likely to experience clinical deterioration or hospitalisation compared with placebo, although analysis of hospitalisation-only data was not statistically significant.[1068]

  • The TOGETHER trial found that fluvoxamine reduced the need for hospitalisation (5% absolute risk reduction) among high-risk patients compared with placebo.[1069]

  • A preliminary double-blind, randomised 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.[1070]

  • A prospective cohort study in the setting of a mass outbreak found that fluvoxamine may prevent clinical deterioration requiring hospitalisation and symptoms persisting beyond 2 weeks.[1071]

Consult local drug formulary for information about contraindications, cautions, adverse effects, and drug interactions before prescribing this drug.

Inhaled corticosteroids

Inhaled budesonide is undergoing clinical trials and shows promise.[1072] It is thought to modulate the inflammatory pathways in the upper respiratory tract and circulation following infection.[1073] Inhaled budesonide is already approved in some countries for indications such as asthma and COPD, but is off-label for this indication.

The UK National Institute for Health and Care Excellence only recommends inhaled budesonide as part of a clinical trial.[20]

  • Trial evidence suggests some benefit in reducing time to recovery. However, evidence suggests there is no statistically significant difference for the outcomes of hospitalisation and death, or need for mechanical ventilation in people having inhaled budesonide and usual care compared with usual care alone. Evidence is limited and further research is required.

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.[19]

  • The Infectious Diseases Society of America suggests against inhaled corticosteroids in patients with mild to moderate disease, except in the context of a clinical trial.[510]

Evidence is emerging.

  • A Cochrane review found that inhaled corticosteroids (budesonide and ciclesonide) probably reduced the combined end point of admission to hospital or death and increased the resolution of initial symptoms at day 14 in people with mild symptoms (moderate‐certainty evidence). However, low‐certainty evidence suggests that corticosteroids make little to no difference in all‐cause 30-day mortality and may decrease duration to symptom resolution.[1074]

  • 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.[1075] 

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.[20]

  • 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 hospitalised patients for azithromycin) unless there are additional indications for which their use remains appropriate.[1076]

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.[19]

Evidence does not support the use of this treatment.

  • A Cochrane review found that azithromycin did not reduce 28-day all-cause mortality in hospitalised patients compared with standard of care alone (high-certainty evidence). Hospitalised patients with moderate to severe disease did not benefit from azithromycin in terms of clinical worsening or improvement (moderate-certainty evidence). Azithromycin had no beneficial effect in the outpatient setting (low-certainty evidence).[1077]

  • Systematic reviews and meta-analyses have found that azithromycin was not associated with an improvement in hospitalisation rate, intensive care unit admission, need for respiratory support, or mortality rate compared with control.[1078][1079] 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 hospitalised patients compared with usual standard care alone.[1080]

  • 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.[1081]

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.[1082][1083][1084][1085]

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.[19]

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.[1086]

Evidence is emerging.

  • 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.[1087]

  • Meta-analyses have found that vitamin D might be associated with improved clinical outcomes, including decreased risk of intensive care admission and mortality, and that there may be a potential role for vitamin D supplementation in reducing disease severity, but noted that additional evidence is required.[1088][1089][1090][1091][1092]

  • 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.[1093]

  • A pilot randomised controlled trial found that high-dose calcifediol significantly reduced the need for intensive care unit treatment in hospitalised patients, and may improve clinical outcomes.[1094]

Vitamin C

Vitamin C supplementation has shown promise in the treatment of viral infections.[1095] High-dose intravenous vitamin C is being trialled in some centres for the treatment of severe disease.[1096]

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.[19]

Evidence is emerging.

  • A systematic review of six randomised controlled trials found that vitamin C did not reduce mortality, length of stay in hospital or intensive care unit, or need for invasive mechanical ventilation. However, there were various limitations to the study (e.g., heterogeneity of dose and route). Further well-designed randomised controlled trials are required.[1097]

  • A systematic review and meta-analysis found that length of hospital stay and mortality was not significantly different between patients taking high-dose intravenous vitamin C and those not taking it. Evidence supporting the therapeutic use of high-dose intravenous vitamin C is lacking and further studies are required.[1098]

Lung transplantation

Lung transplantation has been used as salvage therapy in patients with COVID-19–associated acute respiratory distress syndrome (ARDS) who do not recover despite maximum ventilatory support, extracorporeal membrane oxygenation, and optimal medical care. Between August 2020 and September 2021, 214 lung transplantations were performed in the US (7% of lung transplants nationally). The 3-month survival among these patients approached that among patients who underwent lung transplantation for reasons other than COVID-19.[1099] In a retrospective case series of 30 patients with COVID-19–associated ARDS who underwent lung transplantation, survival was 100% (median follow-up 351 days).[1100]

Clinical trials

Various other treatments are in clinical trials around the world.

International trials to identify treatments that may be beneficial, such as the World Health Organization’s Solidarity trial, and the UK’s randomised evaluation of COVID-19 therapy (RECOVERY) trial, are ongoing.

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