Treatment and pharmaceutical prophylaxis of COVID-19
(Latest update 21 December 2021)
Several medicinal products have been studied to assess their safety and efficacy as potential agents for pharmaceutical prophylaxis or treatment of COVID-19. These include corticosteroids, antivirals, systemic interferons, monoclonal antibodies against components of the immune system such as interleukin-6 (IL-6), other immune modulators, and monoclonal antibodies against components of SARS-CoV-2. Clinical trials of therapeutic interventions for COVID-19 have focused on adult patients, and therefore limited data exist on the treatment of COVID-19 in children.
Potential treatments should be carefully assessed in randomised controlled trials (RCTs). In 2020, several large-scale, multi-centre trials were organised using an appropriately robust methodology for assessment of potential therapeutics. These included the World Health Organization (WHO) Solidarity Trial, the UK RECOVERY trial group, several studies by United States (US) National Institutes of Health (NIH), and national/international trials in Europe [1-3].
Since September 2020, the use of systemic corticosteroids has been included in WHO’s ‘Therapeutics and COVID-19: living guideline’ as a strong recommendation for COVID-19 patients requiring oxygen, based on a systematic review and meta-analysis of the results of eight RCTs . Systemic corticosteroids are not recommended for patients with non-severe COVID-19 infection [4-6].
Paediatric studies in France and the US on children hospitalised for multisystem inflammatory syndrome in children (MIS-C), showed that the use of intravenous immunoglobulin (IVIG) and methylprednisolone, was associated with more favourable disease outcomes than treatment with IVIG alone [7,8].
A new recommendation to use corticosteroids in addition to supportive care for hospitalised children aged 0-18 years diagnosed with MIS-C was published by WHO on 23 November 2021 .
In a RCT of the inhaled corticosteroid budesonide, in adults with mild COVID-19, the frequency of urgent care visits was 3% in the budesonide arm, compared to 15% in the standard care arm (p=0.009) .
Tocilizumab and sarilumab
Tocilizumab and sarilumab are monoclonal antibodies that inhibit the pro-inflammatory action of interleukin 6 (IL-6) by blocking its receptors.
In July 2021, WHO included a strong recommendation for the use of IL-6 receptor blockers in severe and critically ill COVID-19 cases, based on the findings of multiple RCTs . According to the review, IL-6 receptor blockers:
- reduce mortality (OR 0.86; 95% confidence interval (CI) 0.79–0.95);
- reduce the need for invasive mechanical ventilation (OR 0.72; 95% CI 0.57-0.90);
- may reduce the duration of mechanical ventilation (−1.2 days; 95% CI -2.3 to −0.1 days);
- may reduce the duration of hospitalisation (−4.5 days; 95% CI -6.7 to −2.3 days).
In December 2021, EMA recommended extending the indication of tocilizumab to include the treatment of adults with COVID-19, who are receiving systemic treatment with corticosteroids and require supplemental oxygen or mechanical ventilation .
Baricitinib, an orally-administered, selective inhibitor of Janus kinases (JAKs) 1 and 2, given in combination with the antiviral remdesivir to hospitalised adults with COVID-19, was associated with a shorter median time to recovery (seven days versus eight days, rate ratio for recovery: 1.16; 95% CI: 1.01–1.32; p=0.03), and 30% higher odds of improvement in clinical status at Day 15 (OR 1.3; 95% CI: 1.0–1.6), than in the control group receiving only remdesivir . A randomised controlled trial of remdesivir in combination with baricitinib showed that patients who received the combination had a shorter recovery time than those who received remdesivir alone (seven versus eight days; p=0.03) . In April 2021, EMA began evaluating an extension of baricitinib usage to include treatment of COVID-19 in hospitalised patients aged 10 years or older who require supplemental oxygen .
Other immunomodulatory monoclonal antibodies, such as the interleukin-1 (IL-1) receptor antagonist anakinra are being studied for the treatment of severe COVID-19. In a large RCT, no evidence of clinical benefit was observed . However, a double-blind, randomised controlled trial (SAVE-MORE) evaluated the efficacy and safety of anakinra in patients with COVID-19 at risk of progressing to respiratory failure, by identifying early increase of soluble urokinase plasminogen activator receptor (suPAR) serum levels . The odds of a worse clinical outcome at Day 28 with anakinra, as compared to placebo, were 0.36 (95% CI 0.26–0.50). The clinical benefit of anakinra treatment was already apparent from Day 14 and continued until Day 28. The relative decrease in mortality was 55%, reaching 80% for patients with possible cytokine storm.
In July 2021, the EMA began evaluating the extension of anakinra usage for the treatment of COVID-19 in adult patients with pneumonia who were at risk of developing severe respiratory failure .
Monoclonal antibodies against SARS-CoV-2
WHO conditionally recommends the combination of the neutralising monoclonal antibodies casirivimab and imdevimab in the treatment of patients with mild-to-moderate COVID-19 infection at high risk of progressing to severe COVID-19 and hospitalisation . It is also recommended for patients with severe or critical COVID-19, under the condition that the patient has seronegative status. This combination can be administered either as an intra-venous infusion or as four subcutaneous injections. In November 2021, the EMA recommended authorisation of this combination of neutralising monoclonal antibodies for use in the EU as treatment of confirmed COVID-19 in adults and adolescents (from 12 years of age and weighing at least 40 kg) who do not require supplemental oxygen, and who are at a high risk of the disease progressing to severe COVID-19 . In November 2021, the FDA also issued an ‘Emergency Use Authorization’ .
Another combination of monoclonal antibodies, bamlanivimab with etesevimab, has been assessed in a randomised phase 3 trial for a cohort of ambulatory patients with mild or moderate COVID-19 who were at high risk of progression to severe disease. By Day 29, 11 (2.1%) of 518 patients in the bamlanivimab-etesevimab group had been hospitalised or died due to COVID-19, compared to 36 (7%) of 517 patients in the placebo group (absolute risk difference −4.8 percentage points; 95% CI: −7.4 to −2.3; relative risk difference 70%; P<0.001). At Day 7, a greater reduction from the baseline in the log viral load was observed among patients who received bamlanivimab plus etesevimab, than among those who received the placebo (difference from placebo in the change from baseline −1.20; 95% CI: −1.46 to −0.94; P<0.001) . Bamlanivimab has also been tested in a randomised phase 3 trial (BLAZE-2) for the prevention of COVID-19 among long-term care facility residents exposed to COVID-19 . After eight weeks of follow-up, residents in the bamlanivimab group had a statistically significant lower frequency of symptomatic COVID-19 than the placebo group (OR 0.43; p<0.001) .
Mutations present in emerging variants of concern, such as the E484K mutation in the B.1.351 and P.1 variants, have been linked to a reduced in vitro susceptibility of SARS-CoV-2 to monoclonal antibodies such as bamlanivimab .
EMA has ended the rolling review of bamlanivimab and etesevimab, after the company Eli Lilly Netherlands BV informed the agency that it was withdrawing from the process .
On 26 March 2021, GlaxoSmithKline PLC and VirBiotechnology Inc. announced the results of the interim analysis of a phase 3 clinical trial of the monoclonal antibody sotrovimab (VIR-7831) for the early treatment of COVID-19 in patients with mild-to-moderate disease and at high risk of hospitalisation. The study showed an 85% reduction in hospitalisation or death among those receiving sotrovimab compared to placebo (p=0.002). Based on these results, the US Food and Drug Administration (FDA) issued an ‘Emergency Use Authorization’ and the EMA recommended the use of sotrovimab to treat confirmed COVID-19 in adults and adolescents (aged >12 years and weighing at least 40 kg) who do not require supplemental oxygen therapy and who are at risk of progressing to severe COVID-19 [25,26].
AstraZeneca received ‘Emergency Use Authorization’ in the US from FDA for AZD7442, a combination of two long-acting antibodies - tixagevimab (AZD8895) and cilgavimab (AZD1061) - for prophylaxis of symptomatic COVID-19 . Data from a randomised, double-blind, placebo-controlled, multi-centre phase 3 trial (PROVENT), showed that a single intramuscular dose of AZD7442 reduced the risk of developing symptomatic COVID-19 by 77%, compared to placebo . The full results are not yet published.
On 11 November 2021, the EMA recommended authorisation of regdanvimab for use in adults with COVID-19 who do not require supplemental oxygen and who are at increased risk of severe disease . The decision was based on the results of a global Phase 3 clinical trial with more than 1 315 people enrolled, which evaluated the efficacy and safety of regdanvimab in 13 countries including Romania, Spain and the US. Regdanvimab significantly reduced the risk of COVID-19 related hospitalisation or death by 72% for patients at high risk of progressing to severe COVID-19 and by 70% for all patients .
The interim results of the WHO Solidarity Trial, an RCT comparing four therapeutic agents to standard care carried out in 405 hospitals across 30 different countries, showed that remdesivir did not have any effect on mortality (relative risk (RR) 0.95; 95% CI: 0.81–1.11; p=0.50) . In addition, the authors did not observe any effect on the time to discharge, although the study was not designed to address this question. Based on a review of this and three other trials which, in total, studied over 7 000 patients, a WHO Guideline Development Group (GDG) panel of international experts concluded that there is currently no evidence that remdesivir improves survival and other outcomes in hospitalised COVID-19 patients and issued a conditional recommendation against the use of remdesivir in these patients, irrespective of disease severity . The ACTT-1 study, a double-blind, placebo-controlled RCT with 1 062 enrolled hospitalised COVID-19 patients, showed that remdesivir was associated with a shorter median recovery time compared to placebo (10 versus 15 days, p<0.001). The 14-day mortality was 6.7% in the group of patients that received remdesivir and 11.9% in the placebo group, but this difference was not statistically significant . A randomised controlled trial, involving 584 patients with moderate COVID-19 from 105 hospitals in Europe, the US and Asia, found a minimal improvement in clinical status in the five-day remdesivir treatment group, but no difference between the 10-day treatment group and standard care . The authors concluded that the findings were of uncertain clinical importance. On 25 June 2020, the EMA Committee for Medicinal Products for Human Use (CHMP) recommended granting remdesivir a conditional marketing authorisation for the treatment of COVID-19 patients with pneumonia requiring supplemental oxygen . More recently, a multicentre, open-label, randomised, controlled trial (DisCoVeRy) that compared remdesivir plus standard care in adult COVID-19 patients with hypoxaemic pneumonia, or requiring oxygen supplementation (n=429) versus standard care only (n=428), did not show any clinical benefit from remdesivir treatment .
Following the recommendation by the EMA, the European Commission granted remdesivir a conditional marketing authorisation for the treatment of COVID-19 in adults with pneumonia who require supplemental oxygen, as well as for the treatment of COVID-19 in adolescents aged ≥12 years and weighing ≥40 kg with analogous clinical presentation . The US FDA has warned against use of remdesivir in combination with hydroxychloroquine . A phase 2/3 open label study (‘CARAVAN’) has begun to evaluate the use of remdesevir in children aged <18 years . The EMA is evaluating the results of the WHO Solidarity Trial .
In a large retrospective analysis of 28 855 patients who had received remdesivir and were matched to 16 687 controls, remdesivir was associated with a reduction in mortality at Days 14 and 28 (HR 0.76 [95%CI: 0.70−0.83] and 0.89 [95%CI: 0.82−0.96], respectively) . Mortality reductions were also seen in the sub-groups of patients not receiving supplemental oxygen, receiving low-flow oxygen, on mechanical ventilation or receiving extracorporeal membrane oxygenation (ECMO).
A randomised controlled trial of remdesivir in combination with the immunomodulatory agent baricitinib showed that patients who received the combination had a shorter recovery time than those who received remdesivir alone (seven versus eight days; p=0.03) . Among patients receiving high-flow oxygen or non-invasive ventilation at enrolment, the recovery time was also shorter in the group receiving the combination than in the group receiving only remdesivir (10 versus 18 days). There was also a non-statistically significant improvement in mortality at 28 days among those who received the combination of baricitinib with remdesivir compared to those who only received remdesivir (5.1% vs 7.8%).
Molnupiravir is an orally bioavailable ribonucleoside analogue that has been shown to be active against RNA viruses, including SARS-CoV-2, in animal models [40,41]. On 26 November 2021, Merck & Co. Inc. and Ridgeback Biotherapeutics announced that molnupiravir reduced the risk of hospitalisation or death, based on the results of the MOVe-OUT trial in at-risk, non-hospitalised adult patients with mild-to-moderate COVID-19 . According to this press release, molnupiravir reduced the risk of hospitalisation or death from 9.7% (68/699) in patients who received the placebo to 6.8% (48/709) in patients who received molnupiravir, for an absolute risk reduction of 3.0% (95% CI: 0.1-5.9; p=0.0218) and a relative risk reduction of 30% (relative risk 0.70; 95% CI 0.49-0.99). Nine deaths were reported in the placebo group, and one in the molnupiravir group . Merck & Co. Inc. submitted an application for ‘Emergency Use Authorization’ to the US FDA . Although molnnupiravir is not currently authorised in the EU, EMA advised that it can be used to treat adults with COVID-19 who do not require supplemental oxygen and who are at increased risk of developing severe COVID-19. It should be administered within five days of symptom onset .
In a press release on 14 December 2021, Pfizer presented final data of a Phase 2/3 trial on the oral antiviral PaxlovidTM, a combination of nirmatrelvir, an investigational SARS-CoV-2 viral protease inhibitor that blocks the replication of SARS-CoV-2, with ritonavir .
The results of this randomised study of 2 246 adults showed significantly reduced hospitalisation and death rates of non-hospitalised adult COVID-19 patients who were at high risk of progressing to severe illness. It showed an 89% reduction in risk of COVID-19-related hospitalisation or death compared to placebo in patients treated within three days of symptom onset. Adverse events were mostly mild. Patients who received PaxlovidTM had fewer serious adverse events (1.6% vs. 6.6%) than patients in the placebo group. The data have been shared with the FDA as part of an ongoing rolling submission for `Emergency Use Authorization’. The EMA has started reviewing available data .
The orally-administered antiviral drug favipiravir is an inhibitor of viral RNA polymerase that was initially developed against influenza. In a randomised, open-label phase 3 trial, favipiravir treatment resulted in 62.5% clearance of the virus within four days compared to 30% with standard care (control group) . In another randomised, open label phase 3 clinical trial involving 150 adults with mild-to-moderate COVID-19, there was no difference in the median time to the cessation of viral shedding between the favipiravir group (five days) and the standard care group (seven days; p=0.129). However, the median time to clinical cure was shorter in the favipiravir group (three days) than in the standard care group (five days, p=0.030) .
COVID-19 convalescent plasma
COVID-19 convalescent plasma (CCP) therapy is the administration of plasma with antibodies from patients who have recovered from COVID-19, which can be both a prophylactic and therapeutic option. Initial results from various non-RCTs and expanded emergency use did not show any increase in adverse effects after CCP treatment . Another study suggested that the transfusion of CCP containing a high titre of neutralising antibodies could be effective in reducing the mortality of hospitalised patients . However, several subsequent studies failed to show beneficial effects from CCP. In an RCT involving 333 hospitalised patients with COVID-19, no difference was observed in mortality or other clinical outcomes between the CCP and placebo groups at Day 30 . The PLACID study, an RCT involving patients transfused with CCP containing low neutralising antibody titres, found no difference in 28-day mortality or progression to severe disease among patients with moderate COVID-19 . The RECOVERY Collaborative group published results from 5 795 hospitalised patients who received high-titre CCP and found no significant difference in 28-day mortality compared to the control group .
A Cochrane living systematic review on the use of CCP for COVID-19 patients reviewed nine RCTs (12 875 patients) to assess the effectiveness of CCP compared to placebo or standard care alone. CCP did not reduce all‐cause mortality up to Day 28 post diagnosis (RR 0.98, 95% CI 0.92-1.05). The review concluded with high certainty that CCP does not reduce mortality and has little to no impact on clinical improvement in individuals with moderate-to-severe disease. It also concluded with less certainty that CPP has no impact on the duration of mechanical ventilation and does not reduce the need for mechanical ventilation .
On 7 December 2021, WHO published a strong recommendation against the use of CCP in patients with non-severe COVID-19, while it should only be used within clinical trials for severe and critical COVID-19 patients .
Other therapeutic agents against COVID-19
A double-blind RCT (COLCORONA), involving 4 488 non-hospitalised COVID-19 patients with risk factors for severe disease, showed that oral colchicine, a widely-available anti-inflammatory agent, was associated with a decreased risk of ‘hospitalisation or death’ from 6.0% to 4.6% (OR 0.75; 95% CI: 0.57–0.99; p=0.04) among 4 019 patients with PCR-confirmed COVID-19 . On 22 January 2021, the Montreal Health Institute announced in a press release that colchicine decreased the risk of death or hospitalisation by 21% compared to placebo among 4 488 patients with COVID-19. The full results of this trial are not yet available .
However, the RECOVERY randomised trial of 5 610 patients between November 2020 and March 2021 showed that colchicine treatment was not associated with reductions in 28-day mortality, duration of hospital stay, or risk of progression to invasive mechanical ventilation or death in adults hospitalised for COVID-19 .
On 26 February 2021, the results from SARPAC (NCT04326920), an open-label, prospective, RCT of inhaled recombinant human Granulocyte-Macrophage Colony-Stimulating Factor (rhuGM-CSF or sargramostim) were announced. Among 81 patients with hypoxemic COVID-19 respiratory failure, oxygenation improved by at least 33% in 54% of patients in the sargramostim plus standard care group, versus 26% in the standard care only group (p=0.147) [60,61]. The results of the study have not yet been peer-reviewed.
Data from in vitro experimental studies showed that hydroxychloroquine and chloroquine had an inhibitory effect on SARS-CoV-2 .
RCTs, such as the WHO Solidarity Trial and the RECOVERY trial, did not find any evidence of a benefit from hydroxychloroquine for the treatment of COVID-19 and discontinued their hydroxycholoquine arm. Results of the RECOVERY trial, comparing 1 542 patients randomised to receive hydroxychloroquine with 3 132 patients receiving standard care, did not find any difference in mortality, hospital stay or other outcomes between the two groups .
Two clinical trials that investigated the effect of hydroxycholoquine when started early (within four to five days of symptom onset) in non-hospitalised COVID-19 patients with mild symptoms did not show any statistically significant effect on symptom severity . An RCT for post-exposure prophylaxis, involving 821 individuals with household or occupational exposure to confirmed COVID-19 cases, did not show a statistically significant difference in the incidence of illness compatible with COVID-19 between the group receiving hydroxychloroquine and the group receiving placebo .
WHO recommends against the use of hydroxychloroquine for treatment of COVID-19 .
The British COPCOV RCT is still ongoing and aims to enrol 40 000 healthcare workers and other at-risk staff around the world to study the efficacy of hydroxychloroquine as a pharmaceutical prophylactic for COVID-19 .
Lopinavir/ritonavir is a combination of antiviral agents used for the treatment of HIV infection. An RCT of lopinavir/ritonavir in 199 COVID-19 patients in China did not show any statistically-significant favourable effect on the clinical course or mortality when compared to standard care . Similarly, the RECOVERY trial, that randomised 1 616 patients to lopinavir-ritonavir and compared them with 3 424 patients randomised to standard care, did not show any beneficial effect of lopinavir/ritonavir on survival, the clinical course of disease or the length of hospital stay . The study did not include a sufficient number of subjects under invasive mechanical ventilation to allow an analysis of the effect of lopinavir/ritonavir in mechanically ventilated patients, due to the difficulty of administering the drug in such cases. The WHO Solidarity Trial discontinued its lopinavir/ritonavir arm after interim analysis of the results and WHO’s therapeutic guidelines recommend against using this antiviral for any COVID-19 case severity since December 2020 .
Ivermectin is an antiparasitic agent that has been suggested as having some antiviral properties in vitro. However, it has not been shown to be effective against COVID-19 in clinical studies so far . An RCT of the antiparasitic drug ivermectin against placebo in COVID-19 patients with mild disease and symptoms of up to seven days, showed that ivermectin did not improve the time to resolution of symptoms .
Preliminary results from a double-blind RCT that included non-critical hospitalised patients with COVID-19 did not show any statistically significant difference in the duration of hospitalisation, respiratory deterioration or death between the ivermectin group and the hydroxychloroquine or standard care groups . Since March 2021, WHO’s ‘Therapeutics and COVID-19: living guideline’ recommends against the use of ivermectin, except in the context of a clinical trial .
Use of antibiotics in patients with COVID-19
Antibiotics are indicated for the treatment of suspected or confirmed bacterial co-infections or secondary infections in patients with COVID-19, and are not indicated for patients with mild COVID-19 . However, the prevalence of bacterial co-infection and secondary bacterial infection in patients with COVID-19 seems to be relatively low. The prevalence of secondary bacterial infections is higher in patients with severe COVID-19 who are hospitalised and/or mechanically ventilated than in other patients [72-74] . On the other hand, there is need for more clarity in defining secondary bacterial infections in COVID-19 patients .
A retrospective cohort study showed that 7.2% of patients with COVID-19 also had a bacterial infection. Community-acquired co-infection at the time of COVID-19 diagnosis was uncommon (3.1%) and mainly caused by Streptococcus pneumoniae and Staphylococcus aureus. Hospital-acquired bacterial secondary infections, mostly caused by Pseudomonas aeruginosa and Escherichia coli, represented 59.5% of microbiologically documented bacterial infections and were diagnosed in 3.8% of patients. Patients with community-acquired co-infections or hospital-acquired super-infections had worse outcomes than COVID-19 patients without bacterial infection .
In one meta-analysis, which was conducted at the beginning of the COVID-19 pandemic, bacterial co-infection was identified in 3.5% of patients (95%CI: 0.4–6.7%) and secondary bacterial infection in 14.3% of patients (95%CI: 9.6–18.9%). The overall proportion of COVID-19 patients with a bacterial infection was 6.9% (95% CI: 4.3–9.5%). Bacterial infection was more common in critically-ill patients (8.1%; 95% CI: 2.3–13.8%) .
Another systematic review and meta-analysis indicated that the prevalence of bacterial co-infection was 4% (95% CI: 1–8%) and that of bacterial super-infection 6% (95% CI: 2–11%). Patients with bacterial super-infection had a higher prevalence of mechanical ventilation (21%; 95% CI: 13–31% versus 7%; 95% CI: 2–15%) and a longer average length of hospital stay (12.5 days, standard deviation (SD): 5.3 versus 10.2 days, SD: 6.7] than patients with bacterial co-infection .
In a comprehensive review of data from post-mortem studies, potential bacterial lung super-infection was evident at post-mortem examination in 32% of patients who died with COVID-19 (proven, 8%; possible, 24%), but bacterial lung super-infection was uncommon as the cause of death .
The antibiotic azithromycin has been postulated as having antiviral and anti-inflammatory activity and has been studied for the treatment of COVID-19. However, multiple studies have not identified any clinical benefit [78-80].
Despite the low risk of bacterial infection in patients with COVID-19 (see above), antibiotic prescribing is common in COVID-19 patients. A rapid review and meta-analysis showed that the prevalence of antibiotic prescribing in COVID-19 patients was 74.6% (95% CI: 68.3–80.0%). Antibiotic prescribing was related to increasing patient age (OR 1.45 per 10-year increase; 95% CI: 1.18–1.77) and an increasing proportion of patients requiring mechanical ventilation (OR 1.33 per 10% increase; 95% CI: 1.15–1.54). The proportion of COVID-19 patients being prescribed antibiotics was 59.3% in the mixed inpatient/outpatient setting, 74.8% in the inpatient hospital setting and 86.4% in the intensive care unit setting . An observational study of 5 853 hospitalised COVID-19 adult and paediatric patients at a single centre in New York City found that 4 130 (70.6%) patients received at least one dose of antibiotics. Moreover, in patients hospitalised with bacterial co-infections, the administration of more than three classes of antibiotics was observed in 70% of patients .
The widespread overuse of antibiotics observed among COVID-19 patients during the pandemic runs the risk of increasing antimicrobial resistance in both inpatient and outpatient settings. In the context of the COVID-19 pandemic, antimicrobial stewardship should be strengthened to ensure appropriate use of antibiotics and other antimicrobials in COVID-19 patients.