Coronavirus disease 2019 (COVID-19)

Vilobelimab

Vilobelimab is an investigational, first-in-class, intravenous anti-C5a monoclonal antibody. C5a plays a role in severe lung injury. A phase 3, double-blind, randomised placebo-controlled trial found that vilobelimab, in addition to standard of care, reduced mortality at 28 and 60 days in critically ill patients on invasive mechanical ventilation (absolute risk reduction of 11%) compared with placebo.[776] The US Food and Drug Administration has issued an emergency-use authorisation for the use of vilobelimab for the treatment of hospitalised adults when initiated within 48 hours of receiving invasive mechanical ventilation or extracorporeal membrane oxygenation.[777] Despite its authorisation, guidelines do not currently include recommendations either for or against vilobelimab for the treatment of COVID-19.

Anakinra

Anakinra is an interleukin-1 inhibitor that is approved in Europe for adults with COVID-19 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. It is authorised under an emergency-use authorisation in the US for the same indication. Guidelines suggest against the routine use of anakinra for the treatment of COVID-19.[398] Systematic reviews and meta-analyses have found that anakinra may reduce mortality and the need for invasive mechanical ventilation in hospitalised patients, particularly those with C-reactive protein levels >100 mg/L, compared with standard care alone.[778][779][780] However, a Cochrane review did not find evidence for an important beneficial clinical effect of interleukin-1 inhibitors , and the evidence is uncertain for several outcomes. Anakinra probably results in little or no improvement in symptoms at 28 days after treatment (moderate-certainty evidence). It is uncertain whether anakinra makes a difference to the number of deaths at 28 days after treatment (low-certainty evidence).[781]

Colchicine

Colchicine is an anti-inflammatory agent that downregulates multiple pro-inflammatory pathways. Guidelines recommend against the use of colchicine for the treatment of COVID-19.[398][401][402] 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.[782]

Convalescent plasma

High-titre convalescent plasma is a blood product that contains high titres of antibodies to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) from patients who have recovered. Guidelines recommend against the use of convalescent plasma for the treatment of hospitalised patients with COVID-19, except in the context of a clinical trial.[398][402] Guideline recommendations in patients with non-severe disease are conflicting. Some guidelines recommend it in select patients (e.g., outpatients who are at high risk for progression to severe disease who have no other treatment options).[398][783] Other guidelines recommend against its use in these patients.[402] A Cochrane review found that convalescent plasma does not reduce all-cause 28-day mortality, and has little to no impact on measures of clinical improvement for the treatment of moderate to severe disease, compared with placebo or standard care alone (high-certainty evidence).[784] A living systematic review and network meta-analysis found that convalescent plasma may not confer any meaningful benefit in patients with any disease severity, but whether high-titre convalescent plasma confers any benefit remains uncertain.[785] 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 and hospitalisation, especially in immunocompromised people, and when trials with low-titre convalescent plasma were removed from the analyses.[786][787][788][789][790][791][792][793]

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. A Cochrane review found that IVIG may have little to no impact on mortality and clinical improvement and worsening compared with standard therapy in patients with moderate to severe disease, but may increase adverse events. However, the evidence is uncertain and studies were conducted before the vaccine roll-out and the emergence of variants of concern.[794] A living systematic review and network meta-analysis found that IVIG may not confer any meaningful benefit in patients with any disease severity.[785] However, other meta-analyses have found that IVIG may reduce mortality in patients with severe or critical disease.[795][796]

Granulocyte-macrophage colony-stimulating factor inhibitors

Investigational granulocyte-macrophage colony-stimulating factor (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. Randomised controlled trials have shown positive results for lenzilumab, but not mavrilimumab.[797][798] A meta-analysis found that GM-CSF inhibitors may reduce the incidence of mechanical ventilation and decrease mortality, but evidence is limited and further studies are required.[799]

Stem cell therapy

Mesenchymal stem cells are an investigational product that have been studied for their immunomodulatory properties. Systematic reviews and meta-analyses have found that mesenchymal stem cells may reduce the incidence of adverse events and mortality in patients with severe or critical disease. However, evidence is limited.[800][801][802]

Interferons

Interferons are a family of cytokines with antiviral properties. The WHO Solidarity trial found that interferon beta appears to have little or no effect on hospitalised patients, as indicated by overall mortality, initiation of ventilation, and duration of hospital stay.[803] 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.[804] A randomised controlled trial found that a single dose of pegylated interferon lambda reduced the incidence of hospitalisation or an emergency department visit compared with placebo, among predominantly vaccinated outpatients.[805]

Ivermectin

Ivermectin is a broad-spectrum antiparasitic agent that has shown to be effective against SARS-CoV-2 in vitro.[806] Guidelines do not recommend ivermectin for the treatment of COVID-19, except in the context of a clinical trial for severe or critical disease (in research settings only).[398][401][402] There is insufficient evidence to be clear to what extent ivermectin is helpful or harmful. For most key outcomes, including mortality, mechanical ventilation, hospital admission, duration of hospitalisation, and viral clearance, the evidence is of very low certainty.[654][655] Data from meta-analyses are conflicting. A meta-analysis of 24 randomised controlled trials found that ivermectin provided a significant survival benefit (moderate-certainty evidence), and a likely clinical benefit in terms of improvement and deterioration (low-certainty evidence). Overall, the evidence suggested that early use may reduce morbidity and mortality.[807] Other meta-analyses also support an improvement in clinical outcomes, although the quality of evidence was very low to low.[808][809][810][811][812] However, there are other meta-analyses that have found that ivermectin does not reduce all-cause mortality or result in improvement in other clinical outcomes.[813][814][815][816] A Cochrane review found that ivermectin has no beneficial effect in outpatients (low- to high-certainty evidence). It also has no beneficial effect on clinical improvement or viral clearance in inpatients, but the evidence for whether it prevents death or clinical worsening in inpatients is uncertain (low-certainty evidence).[817]

Fluvoxamine

Fluvoxamine is a selective serotonin-reuptake inhibitor that has anti-inflammatory and possible antiviral effects. Guidelines recommend against the use of fluvoxamine for the treatment of COVID-19, except in the context of a clinical trial.[398][402] A Cochrane review found that fluvoxamine (in addition to standard care) may slightly reduce 28-day all-cause mortality and reduce the risk of hospital admission or mortality in patients with mild disease, compared with standard care plus placebo (low-certainty evidence).[818] A meta-analysis of randomised controlled trials, including the TOGETHER trial, 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.[819]

Sabizabulin

Sabizabulin is an investigational drug that binds to the microtubules in cells (similar to colchicine), thereby interfering with the lifecycle of the SARS-CoV-2 virus, and has antiviral and anti-inflammatory effects. The European Medicines Agency has started a review of the available data on the use of sabizabulin for the treatment of COVID-19.[820] The FDA voted against an emergency-use authorisation for use in hospitalised patients with moderate to severe infection. However, the manufacturer plans to continue late-stage development of the drug. Interim results from a small phase 3 trial (204 patients) found that sabizabulin was associated with a reduction in mortality compared with placebo (45% versus 20%).[821]

VV116 (oral remdesivir)

An oral formulation of remdesivir, known as VV116 (a remdesivir derivative), is currently in development. Guidelines recommend against the use of VV116 for the treatment of COVID-19, except in the context of a clinical trial.[402] A phase 3 randomised controlled trial found that a 5-day course of VV116 was non-inferior to nirmatrelvir/ritonavir in shortening time to sustained clinical recovery in symptomatic adults with mild to moderate disease who were at risk for progression to severe disease, with fewer safety concerns (during the Omicron period).[822] A phase 3 randomised controlled trial found that a 5-day course of VV116 significantly reduced the time to sustained clinical symptom resolution in patients with mild to moderate disease, regardless of the presence of high-risk factors for progression to severe disease or vaccination status, compared with placebo.[823]

Ensitrelvir

An investigational novel oral antiviral that works by selectively inhibiting viral 3CL protease. It is currently approved in Japan under an emergency regulatory approval, but is not approved in other countries. Ensitrelvir has demonstrated in vitro antiviral activity against the Omicron BA.4 and BA.5 subvariants.[824] A phase 2/3 randomised controlled trial found that ensitrelvir reduced the time to resolution of five typical Omicron-related symptoms (by approximately 1 day) compared with placebo in patients with mild to moderate disease treated in less than 72 hours of disease onset.[825][826] Several other phase 3 clinical studies are either ongoing or planned. The US Food and Drug Administration has granted fast-track designation to ensitrelvir.

Olgotrelvir

An investigational oral SARS-CoV-2 main protease (Mpro) inhibitor that has a broad spectrum of antiviral activity, including against the original SARS-CoV-2 virus and the Omicron variant. Olgotrelvir avoids the concomitant use of the CYP3A4 inhibitor ritonavir, lowering the risk of drug-drug interactions compared with nirmatrelvir/ritonavir. A phase 3 trial has been completed.[827]

Simnotrelvir

An investigational oral 3-chymotrypsin-like protease inhibitor antiviral. A phase 2/3 double-blind, randomised, placebo-controlled trial found that early administration of simnotrelvir plus ritonavir significantly shortened the time to the resolution of symptoms and reduced viral load at day 5 in adults, compared with placebo.[828]

Bemnifosbuvir

An investigational oral direct-acting antiviral. Bemnifosbuvir targets SARS-CoV-2 RNA polymerase, and inhibits both RNA-dependent RNA polymerase and nucleotidyltransferase. It is currently being evaluated in the global SUNRISE-3 trial, a randomised, double-blind, placebo-controlled phase 3 trial.[829] The FDA has granted fast-track designation to bemnifosbuvir for the treatment of COVID-19.

Inhaled corticosteroids

Inhaled corticosteroids are thought to modulate the inflammatory pathways in the upper respiratory tract and circulation following infection. Guidelines do not recommend inhaled corticosteroids for the treatment of COVID-19, except in the context of a clinical trial.[398][401] Patients who are on an inhaled corticosteroid for other indications should continue treatment.[398] 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, inhaled corticosteroids make little to no difference in all‐cause 30-day mortality but may decrease duration to symptom resolution (low‐certainty evidence).[830]

Aspirin

Aspirin (and other antiplatelet drugs) are not currently recommended by guidelines, and the evidence for their use is conflicting. The RECOVERY trial found that aspirin was not associated with a reduction in 28-day mortality or a reduced risk of progression to ventilation or death, and was associated with an increased risk of major bleeding events.[831] Other randomised controlled trials also demonstrate no benefit with aspirin (alone or in combination with rivaroxaban).[832][833] However, meta-analyses have found that aspirin may reduce mortality.[834][835] Further randomised controlled trials are required.

Antibiotics

Azithromycin and tetracyclines have been investigated for the treatment of COVID-19. Guidelines recommend against the use of these antibiotics for the treatment of COVID-19 in the absence of another indication for their use.[401] A Cochrane review found that azithromycin did not reduce 28-day all-cause mortality in hospitalised patients compared with standard 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).[836] 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.[837]

Vitamins and minerals and supplements

Vitamin C, vitamin D, and zinc have shown promise in the treatment of viral respiratory tract infections.[838][839][840] Meta-analyses found that high-dose vitamin C reduced the risk of severe disease and mortality.[841][842] However, these findings are inconsistent with other meta-analyses and need to be substantiated by further large-scale studies.[843][844] A Cochrane review found there is currently insufficient evidence to determine the benefits and harms of vitamin D supplementation, and 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.[845] Meta-analyses have found that vitamin D may be associated with improved clinical outcomes, including decreased risk of intensive care admission, reduced length of hospital stay, and decreased mortality, and that there may be a potential role for vitamin D supplementation in reducing disease severity.[846][847][848][849][850][851][852] The UK National Institute for Health and Care Excellence does not recommend supplementation to solely prevent or treat COVID-19, except as part of a clinical trial.[401] Meta-analyses have found that that zinc supplementation may be associated with a decreased risk of mortality.[853][854] A systematic review and meta-analysis of randomised controlled trials found that omega-3 fatty acids may be associated with reduced mortality in hospitalised patients, although the sample size was small.[855]

Probiotics

Probiotics have been used in a variety of conditions, including respiratory infections. A systematic review and meta-analysis found that probiotics were associated with a 51% reduction in reported symptoms, with improvement noted in cough, headache, and diarrhoea.[856] Probiotics may also shorten hospital stay and mortality.[857][858] However, further research is required.

Melatonin

Melatonin has antioxidant, anti-inflammatory, immunomodulatory, and antiviral properties. Small studies have suggested an improvement in symptoms and clinical outcomes.[859][860][861][862] However, further research is required.

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.[863] 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).[864]

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.

Emerging treatments