Treatment and pharmaceutical prophylaxis of COVID-19

(Latest update 5 May 2021)

Background

Several medicinal products have been studied or are currently undergoing clinical trials to assess their safety and efficacy as potential agents for pharmaceutical prophylaxis or treatment of COVID-19. These include corticosteroids, the antiviral nucleotide analogue remdesivir, 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, multicentre trials were organised using an appropriately robust methodology for assessment of potential therapeutics, including the WHO Solidarity Trial, several United States (US) National Institutes of Health (NIH) studies, as well as international and national trials in Europe [1,2].

Antivirals

Remdesivir

The interim results of the WHO Solidarity Trial, a 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) [3]. The authors also 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 more than 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, regardless of disease severity [4]. 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 vs 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 [5]. A randomised controlled trial that enrolled 584 patients with moderate COVID-19 from 105 hospitals in Europe, the U.S. and Asia, found a minimal improvement of clinical status in the five-day remdesivir treatment group, but no difference between the 10-day treatment group and standard care [6]. The authors concluded that the finding was 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 [7].

Following the recommendation by the European Medicines Agency (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 [8]. The U.S. Food and Drug Administration (FDA) has warned against use of remdesivir in combination with hydroxychloroquine [9]. A phase 2/3 open label study (‘CARAVAN’) has started to evaluate the use of remdesevir in children aged <18 years [10]. EMA will evaluate the results of the WHO Solidarity Trial in the coming months [7].

A randomised controlled trial of the immunomodulatory agent baricitinib used in combination with remdesivir showed that patients who received this combination of therapeutics had a shorter recovery time compared to those who received remdesivir alone (7 vs 8 days, p=0.03) [11]. Among patients receiving high-flow oxygen or non-invasive ventilation at enrolment, the recovery time was also shorter in the group receiving the combination compared to the group receiving only remdesivir (10 vs 18 days). There was also a non-statistically significant improvement of 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%).

Favipiravir

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 within four days compared to 30% with standard care (control group) [12]. In another randomised, open label phase 3 clinical trial that enrolled 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), while 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) [13].

Molnupiravir

On 6 March 2021, Merck & Co., Inc. and Ridgeback Biotherapeutics, LP reported the findings from a Phase 2a study of the investigation antiviral molnupiravir [14]. The study included 202 non-hospitalised COVID-19 patients and showed a reduction of time to negativity of infectious virus isolation in nasopharyngeal swabs (0/47 (0%) positive cultures in the molnupiravir group and 6/25 (24%) in the placebo group, p=0.001). Molnupiravir is an orally bioavailable ribonucleoside analogue that has been shown to be active against RNA viruses, including SARS-CoV-2, in animal models [15,16].

Corticosteroids

Systemic corticosteroids

The preliminary results of an open-label RCT of dexamethasone showed that it significantly reduced 28-day mortality, particularly among critically ill COVID-19 patients receiving mechanical ventilation. There was no evidence of benefit for patients who did not require oxygen [17,18]. Based on these findings, the U.S. National Institutes of Health (NIH) recommend the administration of dexamethasone for COVID-19 patients who are either mechanically ventilated or require supplemental oxygen [19]. The Randomised Evaluation of COVID-19 Therapy (RECOVERY) Collaborative group published its findings on 2 100 patients, concluding that the use of dexamethasone resulted in lower 28-day mortality compared to usual care among COVID-19 patients who were receiving either invasive mechanical ventilation or oxygen alone at the time of randomisation, but not among those receiving no respiratory support [18]. Based on a systematic review and meta-analysis of the results of eight RCTs, WHO published a strong recommendation for the use of systemic corticosteroids in severely ill patients with COVID-19, and a conditional recommendation to not use systemic corticosteroids in patients with non-severe COVID-19 [20,21].

On 1 February 2021, the French COVID-19 Paediatric Inflammation Consortium published results on the use of intravenous immunoglobulins (IVIG) and methylprednisolone from a retrospective cohort study of 181 children with suspected multisystem inflammatory syndrome in children (MIS-C). The study showed that treatment with IVIG and methylprednisolone in combination was associated with more favourable disease outcomes than treatment with IVIG alone [22].

Budesonide

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) [23].

Immunomodulatory monoclonal antibodies

Interleukin 6 (IL-6) receptor antagonists. Tocilizumab is a monoclonal antibody that inhibits the pro-inflammatory action of interleukin 6. In the BACC Bay Tocilizumab Trial, a randomised, double-blind placebo controlled trial of 243 patients with COVID-19 in the U.S., tocilizumab was not found to be effective for preventing intubation or death in moderately ill hospitalised COVID-19 patients [24]. However, on 19 November 2020, the investigators of another RCT, the REMAP-CAP trial, announced in a press release that an early analysis of their data showed that treatment with tocilizumab reduced the length of stay in intensive care and mortality among critically ill patients with severe COVID-19 [25]. The full results of this trial have not yet been published.

The RECOVERY Collaborative group published preliminary results indicating that the use of tocilizumab in hospitalised COVID-19 patients with hypoxia and systemic inflammation improved survival rates [26].

A phase 3 RCT of 377 patients, reported favourably on the use of Tocilizumab in hospitalised, not intubated patients with COVID-19 pneumonia. Tocilizumab plus standard care was more efficacious than placebo plus standard care in reducing the likelihood of progression to mechanical ventilation or death among hospitalised patients with COVID-19 pneumonia (hazard ratio 0.56; 95% CI: 0.33–0.97) [27].

In a RCT of tocilizumab versus placebo in 452 hospitalised patients with severe COVID-19 pneumonia, there was no statistically significant difference in clinical status or mortality between the treatment and placebo groups at day 28 [28]. The Infectious Diseases Society of America (IDSA) recommended tocilizumab in addition to standard of care in patients with progressive severe or critical COVID-19 [29]. The recommendation was based on the results of eight RCTs that showed a trend toward reduced mortality at 28 days (RR 0.91; 95% CI: 0.79 –1.04) and a lower relative risk (RR) of clinical deterioration (RR 0.83; 95% CI: 0.77 – 0.89) in the group receiving tocilizumab, than in the placebo group, both in addition to standard care.

The REMAP-CAP study showed that, in addition to standard care with corticosteroids, both tocilizumab and sarilumab (another monoclonal antibody with anti-IL-6 activity) reduced the relative risk of death by 24% when administered to patients within 24 hours of admission to intensive care [30].

A randomised, double-blind, placebo-controlled, multinational phase 3 trial did not show any efficacy of sarilumab in patients admitted to hospital with COVID-19 and receiving supplemental oxygen [31].

Other immunomodulatory monoclonal antibodies, such as the interleukin-1 (IL-1) antagonist anakinra are being studied for the treatment of severe COVID-19; however, no evidence of clinical benefit was observed in a large RCT [32].

Baricitinib, an orally administered, selective inhibitor of Janus kinases (JAKs) 1 and 2, administered in combination with remdesivir, was associated with a shorter median time to recovery (7 days vs 8 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), compared to the control group receiving only remdesivir [11].

Monoclonal antibodies against SARS-CoV-2

Several monoclonal antibodies against components of SARS-CoV-2 have been developed. The interim analysis of two clinical trials of monoclonal antibodies against SARS-CoV-2 given early after disease onset in non-hospitalised patients showed a larger decline in viral loads and a reduced need for medical attention (such as hospitalisation or visit to the emergency department) in patients receiving the antibody treatment than in the placebo group. The first trial is an ongoing phase 2 clinical trial of the monoclonal antibody bamlanivimab (LY-CoV555) which was administered to 452 outpatients who presented with COVID-19 with a median of four days after symptom onset [33]. The second trial was a phase 2 trial of the combination of two monoclonal antibodies, casirivimab and imdevimab (REGN-COV2), administered to 275 patients [34]. 

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 [35]. After eight weeks of follow-up, residents in the bamlanivimab group had statistically significant lower frequency of symptomatic COVID-19 than the placebo group (OR 0.43; p<0.001). The results of this trial are not yet peer-reviewed.

However, 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 reduced in vitro susceptibility of SARS-CoV-2 to monoclonal antibodies such as bamlanivimab [36].

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 VIR-7831 for the early treatment of COVID-19 in patients with mild-to-moderate disease at high risk of hospitalisation. The study showed an 85% reduction in hospitalisation or death among those receiving VIR-7831 compared to placebo (p=0.002). Based on these results, an application for emergency use authorisation was submitted to the U.S. Food and Drug Administration (FDA) [37].

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 and can be both a prophylactic and therapeutic option. Initial results from various non-RCTs and from expanded emergency use did not show any increase of adverse effects after CCP treatment [38], and suggest that the transfusion of CCP containing a high titre of neutralising antibodies could be effective in reducing the mortality of hospitalised patients [39]. However, several studies failed to show beneficial effects of CCP. In a RCT that enrolled 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 [40]. The PLACID study, a RCT with 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 [41]. The RECOVERY Collaborative group published preliminary results on 5 795 hospitalised patients who received high-titre CCP and found no significant difference in 28-day mortality compared to the control group [42].

On the other hand, there is some evidence that early administration of CCP may be beneficial. On 6 January 2021, a small randomised trial of 160 patients in Spain showed that administration of CCP with high titres of antibodies against SARS-CoV-2 to infected patients within 72 hours after the onset of symptoms reduced the risk of progression to severe respiratory disease by 48%. This type of treatment is based on so called ‘super donors’ with very high titres of IgG antibodies against SARS-CoV-2, and the possibility of also using vaccinated donors is discussed by the authors [43]. A retrospective study of 3 082 patients who received CCP in the USA found that the transfusion of plasma with high titres of antibodies against SARS-CoV-2 was associated with a lower risk of death in non-mechanically ventilated patients, particularly in patients who received the treatment within three days of a COVID-19 diagnosis. No benefit was shown for patients who were already on mechanical ventilation [44]. These findings are consistent with other studies on the use of CCP and the antiviral remdesivir, in which early treatment, before critical illness develops, prevented worsening of the disease and possibly death [5,6]. Limiting factors for the use of CCP include the supply of CCP, particularly with high titres of antibodies against SARS-CoV-2, which is only reported in about 20% of convalescing patients [44].

The European Commission together with EU/EEA countries, the European Blood Alliance (EBA), ECDC and other health professionals developed a guidance document on the collection, testing, processing, storage, distribution and monitored use of convalescent plasma for the treatment of COVID-19 patients [45]. The European Commission also set-up an open-access EU/EEA database to collect data on CCP donations and patient outcomes following transfusions of CCP.

Other therapeutic agents

Colchicine

A double-blind RCT (COLCORONA) that enrolled 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 decrease in the risk of hospitalisation or death from 6.0% to 4.6% (OR 0.75; 95% CI: 0.57–0.99; p=0.04) among the 4 019 patients with PCR-confirmed COVID-19. The results of this study have not yet been peer-reviewed [46]. 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 [47].

Preliminary results from a randomised, double-blind trial involving 4 488 non-hospitalised patients with COVID-19 being treated with colchicine showed a reduction in the composite rate of death or hospitalisation (OR 0.79; 95% CI, 0.61-1.03; p=0.08) [46].

Sargramostim

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% patients in the sargramostim plus standard care group versus by only 26% in the standard care only group (p=0.147) [48,49]. The results of the study have not yet been peer-reviewed.

Several other agents have been studied for the pharmaceutical prophylaxis or treatment of COVID-19, but without any demonstrable clinical benefit.

Hydroxychloroquine/chloroquine

Data from in vitro experimental studies indicated that hydroxychloroquine and chloroquine have an inhibitory effect on SARS-CoV-2 [50].

RCTs such as the WHO Solidarity Trial and the RECOVERY trial found did not find any evidence of a benefit of 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 [9].

Two clinical trials that investigated the effect of hydroxycholoquine when started early (within four to five days from symptom onset) in non-hospitalised COVID-19 patients with mild symptoms, did not show any statistically significant effect on symptom severity [51]. A RCT for post-exposure prophylaxis that enrolled 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 [52].

WHO recommends against the use of hydroxychloroquine for treatment of COVID-19 [53].

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 pharmaceutical prophylaxis for COVID-19 [54].

Lopinavir/ritonavir

Lopinavir/ritonavir is a combination of antiviral agents used for the treatment of HIV infection. A 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 [55]. 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 benefit of lopinavir/ritonavir on survival, on the clinical course of disease or on the length of hospital stay [56]. 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 administration of the drug in such cases. The WHO Solidarity Trial discontinued its lopinavir/ritonavir arm after interim analysis of the results [1].

Ivermectin

Ivermectin is an antiparasitic agent that has been suggested to have some antiviral properties in vitro. However, it has not been shown to be effective against COVID-19 in clinical studies so far [57]. A 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 [58].

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 [59].

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 in patients with mild COVID-19 [60]. 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 [61-63] . On the other hand, there is need for more clarity in defining secondary bacterial infections in COVID-19 patients [64].

A retrospective cohort study showed that 7.2% patients with COVID-19 also had a bacterial infection. Community-acquired co-infection at 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 5.1% of bacterial infections and were diagnosed in 4.7% of patients. Overall, mortality was 9.8%. Patients with community-acquired co-infections or hospital-acquired super-infections had worse outcomes [61].

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%) [63].

Another systematic review and metanalysis 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 [62].

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 uncommonly the cause of death [65].

The antibiotic azithromycin has been postulated to have antiviral and anti-inflammatory activity and has been studied for the treatment of COVID-19. However, multiple studies did not identify any clinical benefit [66-68].

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 metanalysis 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 to an increasing proportion of patients requiring mechanical ventilation (OR 1.33 per 10% increase; 95% CI: 1.15–1.54). Antibiotic prescribing was 59.3% in the mixed inpatient/outpatient setting, 74.8% in the inpatient hospital setting and 86.4% in the ICU setting [69]. An observational study of 5 853 hospitalised COVID-19 adult and paediatric patients in a single-centre in New York City found that 4 130 (70.6%) patients received at least one does of antibiotics. Moreover, in patients hospitalised with bacterial co-infections, the administration of more than three classes of  antibiotics was observed in 70% patients [70].

The widespread overuse of antibiotics observed among COVID-19 patients during the pandemic bears the risk of increasing antimicrobial resistance in both outpatient and inpatient 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.

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