Coronavirus Disease 2019 (COVID-19) Treatment & Management

Updated: May 16, 2022
  • Author: David J Cennimo, MD, FAAP, FACP, FIDSA, AAHIVS; Chief Editor: Michael Stuart Bronze, MD  more...
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Treatment

Approach Considerations

Utilization of programs established by the FDA to allow clinicians to gain access to investigational therapies during the pandemic has been essential. The expanded access (EA) and emergency use authorization (EUA) programs allowed for rapid deployment of potential therapies for investigation and investigational therapies with emerging evidence. A review by Rizk et al describes the role for each of these measures, and their importance to providing medical countermeasures in the event of infectious disease and other threats. [24]

Remdesivir, an antiviral agent, was the first drug to gain full FDA approval for treatment of COVID-19 in October 2020. It is indicated for treatment of COVID-19 disease in hospitalized adults and children 12 years and older who weigh at least 40 kg. [25]  An emergency use authorization (EUA) remains in place for treating pediatric patients weighing 3.5 kg to less than 40 kg or children younger than 12 years who weigh at least 3.5 kg. [26] An EUA for convalescent plasma was announced on August 23, 2020. [137]  Numerous other antiviral agents, immunotherapies, and vaccines continue to be investigated and developed as potential therapies. 

The first vaccine to gain full FDA approval was mRNA-COVID-19 vaccine (Comirnaty; Pfizer) in August 2021.  

EUAs have been issued for vaccines, monoclonal-directed antibodies, convalescent plasma, baricitinib (a Janus kinase inhibitor), and tocilizumab (an interleukin-6 inhibitor) in the United States. A full list of EUAs and access to the Fact Sheets for Healthcare Providers are available from the FDA. 

Use of corticosteroids improve survival in hospitalized patients with severe COVID-19 disease requiring supplemental oxygen, with the greatest benefit shown in those requiring mechanical ventilation. [27]

All infected patients should receive supportive care to help alleviate symptoms. Vital organ function should be supported in severe cases. [13]

Early in the outbreak, concerns emerged about nonsteroidal anti-inflammatory drugs (NSAIDs) potentially increasing the risk for adverse effects in individuals with COVID-19. However, in late April, the WHO took the position that NSAIDS do not increase the risk for adverse events or affect acute healthcare utilization, long-term survival, or quality of life. [138]  

Numerous collaborative efforts to discover and evaluate effectiveness of antivirals, immunotherapies, monoclonal antibodies, and vaccines have rapidly emerged. Guidelines and reviews of pharmacotherapy for COVID-19 have been published. [28, 29, 30, 31]  The Milken Institute maintains a detailed COVID-19 Treatment and Vaccine Tracker of research and development progress. 

Searching for effective therapies for COVID-19 infection is a complex process. Gordon and colleagues identified 332 high-confidence SARS-CoV-2 human protein-protein interactions. Among these, they identified 66 human proteins or host factors targeted by 69 existing FDA-approved drugs, drugs in clinical trials, and/or preclinical compounds. As of March 22, 2020, these researchers are in the process of evaluating the potential efficacy of these drugs in live SARS-CoV-2 infection assays. [139]

The NIH Accelerating Covid-19 Therapeutics Interventions and Vaccines (ACTIV) trials public-private partnership to develop a coordinated research strategy has several ongoing protocols that are adaptive to the progression of standard care. 

How these potential COVID-19 treatments will translate to human use and efficacy is not easily or quickly understood. The question of whether some existing drugs that have shown in vitro antiviral activity might achieve adequate plasma pharmacokinetics with current approved doses was examined by Arshad and colleagues. The researchers identified in vitro anti–SARS-CoV-2 activity data from all available publications up to April 13, 2020, and recalculated an EC90 value for each drug. EC90 values were then expressed as a ratio to the achievable maximum plasma concentrations (Cmax) reported for each drug after administration of the approved dose to humans (Cmax/EC90 ratio). The researchers also calculated the unbound drug to tissue partition coefficient to predict lung concentrations that would exceed their reported EC50 levels. [140]

The WHO developed a blueprint of potential therapeutic candidates in January 2020. The WHO embarked on an ambitious global "megatrial" called SOLIDARITY in which confirmed cases of COVD-19 are randomly assigned to standard care or one of four active treatment arms (remdesivir, chloroquine or hydroxychloroquine, lopinavir/ritonavir, or lopinavir/ritonavir plus interferon beta-1a). In early July 2020, the treatment arms in hospitalized patients that included hydroxychloroquine, chloroquine, or lopinavir/ritonavir were discontinued owing to the drugs showing little or no reduction in mortality compared with standard of care. [141]  Interim results released mid-October 2020 found the four aforementioned repurposed antiviral agents appeared to have little or no effect on hospitalized patients with COVID-19, as indicated by overall mortality, initiation of ventilation, and duration of hospital stay. The 28-day mortality was 12% (39% if already ventilated at randomization, 10% otherwise). [142]  

The next phase of the trial, Solidarity PLUS, continued in August 2021. WHO announced over 600 hospitals in 52 countries will participate in testing three drugs (ie, artesunate, imatinib, infliximab). Patients will be randomized to standard of care (SOC) or SOC plus one of the study drugs. The drugs for the trial were donated by the manufacturers; however, approximate costs are $400/day for imatinib, $3,500 for a dose of infliximab, and $50,000 for a course of artesunate. 

The urgent need for treatments during a pandemic can confound the interpretation of resulting outcomes of a therapy if data are not carefully collected and controlled. Andre Kalil, MD, MPH, writes of the detriment of drugs used as a single-group intervention without a concurrent control group that ultimately lead to no definitive conclusion of efficacy or safety. [143]

Rome and Avorn write about unintended consequences of allowing widening access to experimental therapies. First, efficacy is unknown and may be negligible, but, without appropriate studies, physicians will not have evidence on which to base judgement. Existing drugs with well-documented adverse effects (eg, hydroxychloroquine) subject patients to these risks without proof of clinical benefit. Expanded access of unproven drugs may delay implementation of randomized controlled trials. In addition, demand for unproven therapies can cause shortages of medications that are approved and indicated for other diseases, thereby leaving patients who rely on these drugs for chronic conditions without effective therapies. [144]

Drug shortages during the pandemic go beyond off-label prescribing of potential treatments for COVID-19. Drugs that are necessary for ventilated and critically ill patients and widespread use of inhalers used for COPD or asthma are in demand. [145, 146]

It is difficult to carefully evaluate the onslaught of information that has emerged regarding potential COVID-19 therapies within a few months’ time in early 2020. A brief but detailed approach regarding how to evaluate resulting evidence of a study has been presented by F. Perry Wilson, MD, MSCE. By using the example of a case series of patients given hydroxychloroquine plus azithromycin, Wilson provides clinicians with a quick review of critical analyses. [147]

Related articles

The CDC has resources on global COVID-19 on its website.

For more information on investigational drugs and biologics being evaluated for COVID-19, see Treatment of Coronavirus Disease 2019 (COVID-19): Investigational Drugs and Other Therapies.

See the article Coronavirus Disease 2019 (COVID-19) in Emergency Medicine.

The Medscape article Acute Respiratory Distress Syndrome (ARDS) includes discussions of fluid management, noninvasive ventilation and high-flow nasal cannula, mechanical ventilation, and extracorporeal membrane oxygenation.

Some have raised concerns over whether patients with respiratory distress have presentations more like those of high-altitude pulmonary edema (HAPE) than ARDS.

See also the articles Viral Pneumonia, Respiratory Failure, Septic Shock, and Multiple Organ Dysfunction Syndrome in Sepsis.

Medscape resources describing relevant procedures are as follows:

Ventilator application techniques

Ventilator management and monitoring

Respiratory conditions assessment and management

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Medical Care

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Prevention

The FDA has granted EUAs for 3 SARS-CoV-2 vaccines since December, 2020. Two are mRNA vaccines – BNT-162b2 (Pfizer) and mRNA-1273 (Moderna), whereas the third is a viral vector vaccine – Ad26.COV2.S (Johnson & Johnson). 

Avoidance is the principal method of deterrence.

General measures for prevention of viral respiratory infections include the following [13] :

  • Handwashing with soap and water for at least 20 seconds. An alcohol-based hand sanitizer may be used if soap and water are unavailable.
  • Individuals should avoid touching their eyes, nose, and mouth with unwashed hands.
  • Individuals should avoid close contact with sick people.
  • Sick people should stay at home (eg, from work, school).
  • Coughs and sneezes should be covered with a tissue, followed by disposal of the tissue in the trash.

Frequently touched objects and surfaces should be cleaned and disinfected regularly.

Preventing/minimizing community spread of COVID-19

The CDC has recommended the below measures to mitigate community spread. [9, 148, 149]

All individuals in areas with prevalent COVID-19 should be vigilant for potential symptoms of infection and should stay home as much as possible, practicing social distancing (maintaining a distance of 6 feet from other persons) when leaving home is necessary.

Persons with an increased risk for infection—(1) individuals who have had close contact with a person with known or suspected COVID-19 or (2) international travelers (including travel on a cruise ship)—should observe increased precautions. These include (1) self-quarantine for at least 2 weeks (14 days) from the time of the last exposure and distancing (6 feet) from other persons at all times and (2) self-monitoring for cough, fever, or dyspnea with temperature checks twice a day.

On April 3, 2020, the CDC issued a recommendation that the general public, even those without symptoms, should begin wearing face coverings in public settings where social-distancing measures are difficult to maintain in order to abate the spread of COVID-19. [9]

Facemasks

In a 2020 study on the efficacy of facemasks in preventing acute respiratory infection, surgical masks worn by patients with such infections (rhinovirus, influenza, seasonal coronavirus [although not SARS-CoV-2 specifically]) were found to reduce the detection of viral RNA in exhaled breaths and coughs. Specifically, surgical facemasks were found to significantly decreased detection of coronavirus RNA in aerosols and influenza virus RNA in respiratory droplets. The detection of coronavirus RNA in respiratory droplets also trended downward. Based on this study, the authors concluded that surgical facemasks could prevent the transmission of human coronaviruses and influenza when worn by symptomatic persons and that this may have implications in controlling the spread of COVID-19. [150]

In a 2016 systematic review and meta-analysis, Smith and colleagues found that N95 respirators did not confer a significant advantage over surgical masks in protecting healthcare workers from transmissible acute respiratory infections.​ [151]

Investigational agents for postexposure prophylaxis

PUL-042

PUL-042 (Pulmotech, MD Anderson Cancer Center, and Texas A&M) is a solution for nebulization with potential immunostimulating activity. It consists of two toll-like receptor (TLR) ligands: Pam2CSK4 acetate (Pam2), a TLR2/6 agonist, and the TLR9 agonist oligodeoxynucleotide M362.

PUL-042 binds to and activates TLRs on lung epithelial cells. This induces the epithelial cells to produce peptides and reactive oxygen species (ROS) against pathogens in the lungs, including bacteria, fungi, and viruses. M362, through binding of the CpG motifs to TLR9 and subsequent TLR9-mediated signaling, initiates the innate immune system and activates macrophages, natural killer (NK) cells, B cells, and plasmacytoid dendritic cells; stimulates interferon-alpha production; and induces a T-helper 1 cells–mediated immune response. Pam2CSK4, through TLR2/6, activates the production of T-helper 2 cells, leading to the production of specific cytokines. [152]

In May 2020, the FDA approved initiation of two COVID-19 phase 2 clinical trials of PUL-042 at up to 20 US sites. The trials are for the prevention of infection with SARS-CoV-2 and the prevention of disease progression in patients with early COVID-19. In the first study, up to 4 doses of PUL-042 or placebo will be administered to 200 participants via inhalation over a 10-day period to evaluate the prevention of infection and reduction in severity of COVID-19. In the second study, 100 patients with early symptoms of COVID-19 will receive PUL-042 up to 3 times over 6 days. Each trial will monitor participants for 28 days to assess effectiveness and tolerability. [153, 154]

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Antiviral Agents

Remdesivir

Remdesivir (Veklury) was the first drug approved by the FDA for treating the SARS-CoV-2 virus. It is indicated for treatment of COVID-19 disease in hospitalized adults and children aged 12 years and older who weigh at least 40 kg. The broad-spectrum antiviral is a nucleotide analog prodrug. [25]  Full approval was preceded by the US FDA issuing an EUA (emergency use authorization) on May 1, 2020. [155]  Upon approval of remdesivir in adults and adolescents, the EUA was updated to maintain the ability for prescribers to treat pediatric patients weighing 3.5 kg to less than 40 kg or children younger than 12 years who weigh at least 3.5 kg. [26]

The remdesivir EUA was expanded to include moderate disease August 28, 2020. This expands the previous authorization to treat all hospitalized patients with COVID-19 regardless of oxygen status. [156] A new drug application (NDA) for remdesivir was submitted to the FDA in August 2020. A phase 1b trial of an inhaled nebulized version was initiated in late June 2020 to determine if remdesivir can be used on an outpatient basis and at earlier stages of disease. [157]  As of October 1, 2020, remdesivir is available from the distributor (ie, AmerisourceBergen). Wholesale acquisition cost is approximately $520/100-mg vial, totaling $3,120 for a 5-day treatment course.

Inpatient remdesivir

Several phase 3 clinical trials have tested remdesivir for treatment of COVID-19. Positive results were seen with remdesivir after use by the University of Washington in the first case of COVID-19 documented on US soil in January 2020. [158] An adaptive randomized trial of remdesivir coordinated by the National Institute of Health (NCT04280705) was started first against placebo, but additional therapies were added to the protocol as evidence emerged and treatment evolved. The first experience with this study involved passengers of the Diamond Princess cruise ship in quarantine at the University of Nebraska Medical Center in February 2020 after returning to the United States from Japan following an on-board outbreak of COVID-19. [159] Trials of remdesivir for moderate and severe COVID-19 compared with standard of care and varying treatment durations are ongoing.

The initial EUA for remdesivir was based on preliminary data analysis of the Adaptive COVID-19 Treatment Trial (ACTT), and was announced April 29, 2020. The final analysis included 1,062 hospitalized patients with advanced COVID-19 and lung involvement, showing that patients treated with 10-days of remdesivir had a 31% faster time to recovery than those who received placebo (remdesivir, 10 days; placebo, 15 days; P < 0.001). Patients with severe disease (n = 957) had a median time to recovery of 11 days compared with 18 days for placebo. A statistically significant difference was not reached for mortality by day 15 (remdesivir 6.7% vs placebo 11.9%) or by day 29 (remdesivir 11.4% vs placebo 15.2%). [160]  

The final ACTT-1 results for shortening the time to recovery differed from interim results from the WHO SOLIDARITY trial for remdesivir. These discordant conclusions are complicated and confusing as the SOLIDARITY trial included patients from ACTT-1. [142]   An editorial by Harrington and colleagues [161] notes the complexity of the SOLIDARITY trial and the variation within and between countries in the standard of care and in the burden of disease in patients who arrive at hospitals. The authors also mention that trials solely focused on remdesivir were able to observe nuanced outcomes (ie, ability to change the course of hospitalization), whereas the larger, simple randomized SOLIDARITY trial focused on more easily defined outcomes. 

Similar to the SOLIDARITY trial, the DisCoVeRy open-labeled, multicenter trial did not show clinical benefit from use of remdesivir. The trial was conducted in 48 sited throughout Europe from March 22, 2020 to January 21, 2022. However, among the participants included in the SOLIDARITY trial, 219 (8%) of 2750 participants who were randomly assigned to receive remdesivir and 221 (5.4%) of 4088 randomly assigned to standard of care were shared by the DisCoVeRy trial. These shared patients between the 2 trials accounted for approximately 50% of DisCoVeRy participants (remdesivir plus SOC [n = 429]; SOC alone [n = 428]). Standard of care did not include dexamethasone until October 2021 in this trial. [162]  

The open-label phase 3 SIMPLE trial (n = 397) in hospitalized patients with severe COVID-19 disease not requiring mechanical ventilation showed similar improvement in clinical status with the 5-day remdesivir regimen compared with the 10-day regimen on Day 14 (odds ratio, 0.75). After adjustment for imbalances in baseline clinical status, patients receiving a 10-day course of remdesivir had a distribution in clinical status at Day 14 that was similar to that of patients receiving a 5-day course (P = 0.14). The findings could significantly expand the number of patients who could be treated with the current supply of remdesivir. The trial is continuing with an enrollment goal of 6,000 patients. [163]

Similarly, the phase 3 SIMPLE II trial in patients with moderate COVID-19 disease (n = 596) showed that 5 days of remdesivir treatment had a statistically significant higher odds of a better clinical status distribution on Day 11 compared with those receiving standard care (odds ratio, 1.65; P = 0.02). Improvement on Day 11 did not differ between the 10-day remdesivir group and standard of care (P = 0.18). [164]  

The phase 3 PINETREE trial evaluated remdesivir as a 3-day outpatient regimen in high-risk patients with COVID-19. An analysis of 562 patients showed an 87% reduction in risk for COVID-19 related hospitalization or all-cause death by Day 28 for remdesivir (0.7% [2/279]) compared with placebo (5.3% [15/283]) p = 0.008. Remdesivir was also associated with an 81% reduction in the risk of medical visits owing to COVID-19 or all-cause death (1.6% vs 8.3% with placebo; P = 0.002). [165]

Real-world analysis

Three retrospective real-world studies presented at the 2021 World Microbe Forum showed remdesivir-treated hospitalized patients had significantly lower risk for mortality compared with matched controls. The studies included 98,654 patients and results are summarized below. [166]

Aetion and HealthVerity: Remdesivir-treated patients (n = 24,856) had a 23% lower mortality risk compared with controls (n = 24,856), regardless of baseline oxygen requirement from May 1, 2020 to May 3, 2021. Patients who received a 5-day regimen also had a significantly greater likelihood of discharge by day 28. 

Premier Healthcare: Assessed mortality in hospitalized patients who were initiated remdesivir (n=28,855) within the first 2 days of hospitalization versus matched patients not receiving remdesivir (n=16,687) between August and November 2020. Patients were matched on baseline level of oxygenation, hospital, within a 2-month hospital admission period, and all stayed in the hospital for a minimum of 3 days after initiating treatment. Remdesivir-treated patients had a significantly lower risk of mortality at Day 14 (p< 0.0001) and Day 28 (P = 0.003) compared with those not given remdesivir. 

SIMPLE-Severe: Compared outcomes in patients receiving 10-days of remdesivir in the extension phase of the open-label SIMPLE-Severe trial. Regardless of baseline oxygen requirements, treatment with remdesivir results in a 54% lower mortality risk at Day 28 compared with the control group (P< 0.001). 

Remdesivir use in children

Remdesivir emergency use authorization includes pediatric dosing that was derived from pharmacokinetic data in healthy adults. Remdesivir has been available through compassionate use to children with severe COVID-19 since February 2020. A phase 2/3 trial (CARAVAN) of remdesivir was initiated in June 2020 to assess safety, tolerability, pharmacokinetics, and efficacy in children with moderate-to-severe COVID-19. CARAVAN is an open-label, single-arm study of remdesivir in children from birth to age 18 years. [167]

Data were presented on compassionate use of remdesivir in children at the virtual COVID-19 Conference held July 10-11, 2020. Most of the 77 children with severe COVID-19 improved with remdesivir. Clinical recovery was observed in 80% of children on ventilators or ECMO and in 87% of those not on invasive oxygen support. [168]

Remdesivir use in pregnant females

Outcomes in the first 86 pregnant women who were treated with remdesivir (March 21 to June 16, 2020) found high recovery rates. Recovery rates were high among women who received remdesivir (67 while pregnant and 19 on postpartum days 0-3). No new safety signals were observed. At baseline, 40% of pregnant individuals (median gestational age, 28 weeks) required invasive ventilation compared with 95% of postpartum patients (median gestational age at delivery 30 weeks). Among pregnant patients, 93% of those on mechanical ventilation were extubated, 93% recovered, and 90% were discharged. Among postpartum individuals, 89% were extubated, 89% recovered, and 84% were discharged. There was one maternal death attributed to underlying disease and no neonatal deaths. [169]

Data continue to emerge. A case series of five patients describes successful treatment and monitoring throughout treatment with remdesivir in pregnant women with COVID-19. [170]  

Outpatient remdesivir 

Remdesivir gained approval from the FDA for outpatient use in nonhospitalized adults and pediatric patients aged 12 years and older who weigh at least 40 kg with mild-to-moderate COVID-19 who are at high risk for progression to severe disease, including hospitalization or death. Additionally, the EUA for younger children and those weighing less than 40 kg was amended to include outpatient use for mild-to-moderate disease in high-risk individuals. 

Results from the randomized, double-blind, placebo-controlled PINETREE trial supported the expanded indication and EUA. Among 562 outpatients with COVID-19 at high risk for disease progression demonstrated an 87% lower risk of hospitalization or death compared with than placebo (p = 0.008). Overall, 2 of 279 patients who received remdesivir (0.7%) required COVID-19 related hospitalization compared with 15 of 283 patients who received a placebo (5.3%). The study included patients who tested positive for SARS-CoV-2 with symptom onset within the previous 7 days and at least 1 risk factor for disease progression. Patients received either 3 consecutive days of IV remdesivir (200 mg IV on Day 1, then 100 mg on Days 2 and 3) or placebo. [165]  

The outpatient remdesivir dose for children weighing less than 40 kg is 5 mg/kg IV on Day 1, then 2.5 mg/kg on Days 2 and 3. 

Antivirals with EUAs

Nirmatrelvir/ritonavir 

Nirmatrelvir/ritonavir (Paxlovid) was granted an EUA December 22, 2021 for treatment of mild-to-moderate COVID-19 in adults and pediatric patients aged 12 years and older who weigh at least 40 kg who test positive for SARS-CoV-2 virus, and are at high risk for progression to severe COVID-19, including hospitalization or death. Nirmatrelvir inhibits SARS-CoV2-3CL protease, and thereby inhibits viral replication at the proteolysis stage (ie, before viral RNA replication). Nirmatrelvir is combined with low-dose ritonavir to slow its metabolism and provide higher systemic exposure.  

Results from the phase 2/3 trial Evaluation of Protease Inhibition for COVID-19 in nonhospitalized high-risk adults (EPIC-HR) (n = 2,246) showed a relative risk reduction of hospitalization or death by 89.1% with nirmatrelvir plus ritonavir when initiated within 3 days of symptom onset and 88% when initiated within 5 days of symptom onset compared with placebo. Hospitalization through day 28 among patients who received nirmatrelvir/ritonavir within 3 days was 0.7% (5/697 hospitalized with no deaths), compared with 6.5% of patients who received placebo and were hospitalized or died (44/682 hospitalized with 9 subsequent deaths) (p < 0.0001). Similarly, patients who received nirmatrelvir/ritonavir within 5 days had a reduced risk for hospitalization or death for any cause by 88% compared with placebo (p < 0.0001). [171]  

The EPIC-SR (standard risk adults) included unvaccinated adults who were at standard risk as well as vaccinated adults who had 1 or more risk factors for progressing to severe illness. Interim analysis showed 0.6% of patients were hospitalized compared with 2.4% in the placebo group, a 70% reduction in hospitalization and no deaths in the treated population. [172]   

Another clinical trial, EPIC-PEP (Post-Exposure Prophylaxis), administers nirmatrelvir/ ritonavir as postexposure prophylaxis to adult household contacts living with an individual with a confirmed symptomatic SARS-COV-2 infection. [173]    

Molnupiravir

An EUA for molnupiravir was granted on December 23, 2021 for treatment of mild-to-moderate COVID-19 in adults aged 18 years and older who test positive for SARS-CoV-2 virus, and are at high risk for progression to severe COVID-19, including hospitalization or death.

Molnupiravir (MK-4482 [previously EIDD-2801]; Merck) is an oral antiviral agent that is a prodrug of the nucleoside derivative N4-hydroxycytidine. It elicits antiviral effects by introducing copying errors during viral RNA replication of the SARS-CoV-2 virus.

The phase 3 outpatient MOVe-OUT study (n = 1433) found molnupiravir reduced risk for hospitalization or death from 9.7% (68 of 699) in the placebo group to 6.8% (48 of 709) in the molnupiravir group for an absolute risk reduction of 3% (p = 0.02) and a relative risk reduction of 30%. Nine deaths were reported in the placebo group and one in the molnupiravir group. These data are consistent with the interim analysis. [174]  

Molnupiravir is also being evaluated in a phase 3 trial for postexposure prophylaxis for individuals residing in the same household with someone who tests positive for SARS-CoV-2 in the phase 3 MOVE-AHEAD trial. [175]   

Investigational Antivirals 

Opaganib

Opaganib (Yeliva; RedHill Biopharma Ltd) is an orally administered sphingosine kinase-2 (SK2) inhibitor that may inhibit viral replication and reduce levels of IL-6 and TNF-alpha. Nonclinical data indicate both antiviral and anti-inflammatory effects. [176]  A prespecified analysis of phase 2/3 opaganib data in severe COVID-19 demonstrated a significant 70.2% mortality benefit with opaganib by Day 42 when given in addition to best available standard-of-care (SoC), remdesivir and corticosteroids, (6.98% mortality in the opaganib arm versus 23.4% for placebo, p = 0.034). [177]  

Sabizabulin 

Sabizabulin (VERU-111; Veru, Inc) is an oral microtubule depolymerization agent that has broad antiviral activity and has strong anti-inflammatory effects. [178]  A phase 3 trial evaluated sabizabulin in hospitalized patients with moderate-to-severe COVID-19 who were at high risk for ARDS and death. Patients received sabizabulin or placebo in addition to SoC that included remdesivir, dexamethasone, ANI-IL6 receptor antibodies, and JAK inhibitors. Sabizabulin treatment resulted in a 55% relative reduction in deaths (p = 0.0029) in the intent to treat population. The placebo group (n = 52) had a 45% mortality rate compared with sabizabulin-treated patients (n = 98) which had a 20% mortality rate. [179]  

Favipiravir

Favipiravir (Avigan, Reeqonus; Appili Therapeutics) is an oral antiviral that disrupts viral replication by selectively inhibiting RNA polymerase. An adaptive, multicenter, open label, randomized, phase 2/3 clinical trial of favipiravir compared with standard of care I hospitalized patients with moderate COVID-19 was conducted in Russia. Both dosing regimens of favipiravir demonstrated similar virologic response. Viral clearance on Day 5 was achieved in 25/40 (62.5%) patients on in the favipiravir group compared with 6/20 (30%) patients in the standard care group (P = 0.018). Viral clearance on Day 10 was achieved in 37/40 (92.5%) patients taking favipiravir compared with 16/20 (80%) in the standard care group (P = 0.155). [180]  

The phase 3 PRESECO (PREventing SEvere COVID-19) study evaluated early treatment in patients with mild-to-moderate symptoms to prevent disease progression and hospitalization. Enrollment was completed in September 2021. The phase 3 PEPCO (Post Exposure Prophylaxis for COVID-19) study in asymptomatic individuals with direct exposure (within 72 hours) to an infected individual is ongoing. [181]   

AT-527

AT-527 (Atea Pharmaceuticals) is an oral purine nucleotide prodrug designed to inhibit RNA polymerase enzyme. It has demonstrated in vitro and in vivo antiviral activity against several enveloped single-stranded RNA viruses, including human flaviviruses and coronaviruses. Phase 2 interim virology analysis reported in June 2021 included data from 62 of 70 hospitalized patients with moderate COVID-19 symptoms who received the drug or placebo BID for 5 days. On Day 2 of treatment, patients taking AT-527 had an 80% (0.7 log10) greater mean reduction from baseline viral load compared with placebo. No detectable levels of virus were observed at 2 weeks in 47% of the AT-527 group compared with 22% in the placebo group. [182]  

Additional global trials for AT-527 include a phase 2 trial (MOONSONG) and phase 3 trial (MORNINGSKY) in outpatients with mild-to-moderate COVID-19 disease. Another phase 3 trial (MEADOWSPRING) is being conducted as a 6-month long-term follow-on study to evaluate the impact of prior administration of AT-527 on long COVID in patients previously enrolled in MORNINGSKY.

Clinical trials of existing drugs with potential antiviral properties

Nitazoxanide

Nitazoxanide, a broad-spectrum thiazolide antiparasitic agent, is approved in the United States for treatment of Cryptosporidium parvum and Giardia duodenalis infections. The NIH recommends against use of nitazoxanide for treatment of COVID-19, except in a clinical trial.   

Niclosamide 

Niclosamide (FW-1002 [FirstWave Bio]; ANA001 [ ANA Therapeutics]) is an anthelmintic agent used primarily for tapeworms for nearly 50 years. Niclosamide is thought to disrupt SARS-CoV-2 replication through S-phase kinase-associated protein 2 (SKP2)-inhibition, by preventing autophagy and blocking endocytosis. 

A proprietary formulation that targets the viral reservoir in the gut to decrease prolonged infection and transmission has been developed, specifically to decrease gut viral load. It is being tested in a phase 2 trial. [183]  A phase 2/3 trial is testing safety and the potential to improved outcomes and reduce hospital stay by reducing viral load. [184]  

Ivermectin

NIH COVID-19 guidelines for ivermectin provide analysis of several randomized trials and retrospective cohort studies of ivermectin use in patients with COVID-19. The guidelines concluded most of these studies had incomplete information and significant methodological limitations, which make it difficult to exclude common causes of bias.  Ivermectin has been shown to inhibit SAR-COV-2 in cell cultures; however, available pharmacokinetic data from clinically relevant and excessive dosing studies indicate that the SARS-CoV-2 inhibitory concentrations for ivermectin are not likely attainable in humans. [185]  

Chaccour and colleagues raised concerns regarding ivermectin-associated neurotoxicity, particularly in patients with a hyperinflammatory state possible with COVID-19. In addition, drug interactions with potent CYP3A4 inhibitors (eg, ritonavir) warrant careful consideration of coadministered drugs. Finally, evidence suggests that ivermectin plasma levels with meaningful activity against COVID-19 would not be achieved without potentially toxic increases in ivermectin doses in humans. More data are needed to assess pulmonary tissue levels in humans. [186]  

A prospective study (n = 400) of adults with mild COVID-19 were randomized 1:1 to receive ivermectin 300 mcg/kg/day for 5 days or placebo. Ivermectin did not improve time to symptom resolution in patients with mild COVID-19 disease compared with placebo (p = 0.53). [187]  

The Ivermectin Treatment Efficacy in COVID-19 High-Risk Patients (I-TECH) study was an open-label randomized clinical trial conducted at 20 public hospitals and a COVID-19 quarantine center in Malaysia between May 31 and October 25, 2021. Within the first week of patients’ symptom onset, the study included patients aged 50 years and older with laboratory-confirmed SARS-CoV-2, comorbidities, and mild-to-moderate disease. Patients were randomized 1:1 to receive oral ivermectin 400 mcg/kg/day for 5 days plus standard of care (n = 241) or standard of care alone (n = 249). Progression to severe disease did not differ between patients who received ivermectin vs those that did not (p = 0.25). Additionally, no significant differences were observed between the 2 groups regarding mechanical ventilation (p = 0.17), intensive care unit admission (P= 0.79), or 28-day in-hospital death (p = 0.09). [188]  

A double-blind, randomized, placebo-controlled adaptive trial (TOGETHER) in Brazil found ivermectin did not lower incidence of medical admission to a hospital owing to progression of COVID-19 or of prolonged emergency department observation among outpatients with an early diagnosis of COVID-19. Findings were similar in patients who received at least 1 dose and those with 100% adherence to the assigned regimen. [189]  

Other investigational antivirals continue to emerge. 

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Immunomodulators and Other Investigational Therapies

Various methods of immunomodulation are quickly being examined, mostly by repurposing existing drugs, in order blunt the hyperinflammation caused by cytokine release. Interleukin (IL) inhibitors, Janus kinase inhibitors, and interferons are just a few of the drugs that are in clinical trials. Ingraham and colleagues [190]  provide a thorough explanation and diagram of the SARS-CoV-2 inflammatory pathway and potential therapeutic targets. A review of pharmaco-immunotherapy by Rizk and colleagues [191]  summarizes the roles and relationships of innate immunity and adaptive immunity, along with immunomodulators (eg, interleukins, convalescent plasma, JAK inhibitors) prevent and control infection. 

Janus Kinase Inhibitors

Drugs that target numb-associated kinase (NAK) may mitigate systemic and alveolar inflammation in patients with COVID-19 pneumonia by inhibiting essential cytokine signaling involved in immune-mediated inflammatory response. In particular, NAK inhibition has been shown to reduce viral infection in vitro. ACE2 receptors are a point of cellular entry by COVID-19, which is then expressed in lung AT2 alveolar epithelial cells. A known regulator of endocytosis is the AP2-associated protein kinase-1 (AAK1). The ability to disrupt AAK1 may interrupt intracellular entry of the virus. Baricitinib (Olumiant; Eli Lilly Co), a Janus kinase (JAK) inhibitor, is also identified as a NAK inhibitor with a particularly high affinity for AAK1. [192, 193, 194]  

Baricitinib

Baricitinib is the first immunotherapy to gain full FDA approval in May 2022 for treatment of hospitalized adults who require supplemental oxygen, noninvasive or invasive mechanical ventilation, or extracorporeal membrane oxygenation (ECMO). Approval was based on the ACTT-2 and COV-BARRIER trials.

Emergency use authorization (EUA) was issued by the FDA for baricitinib on November 19, 2020, and remains in place for children aged 2-17 years following approval for adults.  

The NIAID Adaptive Covid-19 Treatment Trial (ACTT-2) evaluated the combination of baricitinib (4 mg PO daily up to 14 days) and remdesivir (100 mg IV daily up to 10 days) (515 patients) compared with remdesivir plus placebo (518 patients). Patients who received baricitinib had a median time to recovery of 7 days compared with 8 days with control (P = 0.03), and a 30% higher odds of improvement in clinical status at Day 15. Those receiving high-flow oxygen or noninvasive ventilation at enrollment had a time to recovery of 10 days with combination treatment and 18 days with control (rate ratio for recovery, 1.51). The 28-day mortality was 5.1% in the combination group and 7.8% in the control group (hazard ratio for death, 0.65). Incidence of serious adverse events were less frequent in the combination group than in the control group (16.0% vs. 21.0%; P = 0.03) There were also fewer new infections in patients who received baricitinib (5.9% vs. 11.2%; P =0 .003). [195]  

The COV-BARRIER trial demonstrated baricitinib to be the first immunomodulatory treatment to reduce COVID-19 mortality in a placebo-controlled trial. [196]  Results from the global COV-BARRIER phase 3 trial showed a reduced risk for death in hospitalized patients not on mechanical ventilation who received baricitinib 4 mg daily for up to 14 days when added to standard of care (SOC), compared with SOC alone at Day 28 (38.2% risk reduction in mortality;  (62/764 [8.1%] baricitinib; 101/761 [13.3%] placebo; p = 0.0018). Progression to high-flow oxygen, noninvasive ventilation, or invasive mechanical ventilation did not reach statistical significance for baricitinib plus SOC compared with SOC alone (27.8% vs 30.5%; p = 0.0018). The 60-day all-cause mortality was 10% (n=79) for baricitinib and 15% (n=116) for placebo (p = 0.005). Serious adverse events occurred in 15% of the baricitinib group compared with 18% of those receiving placebo. Serious infections (9% vs 10%) and venous thromboembolic events (3% in each group) were similar between the two groups. [197]  

The COV-BARRIER study was expanded to include patients on mechanical ventilation. Those who received baricitinib plus SOC and on mechanical ventilation or ECMO were 46% less likely to die by Day 28 compared with patients on SOC alone (p = 0.0296). The cumulative proportion among these patients who died by Day 28 was 39.2% (20/51) in the baricitinib arm compared with 58% in the placebo arm (29/50). [198]  

Tofacitinib

Tofacitinib (Xeljanz), another JAK inhibitor, was evaluated in 289 hospitalized patients with COVID-19 pneumonia were randomized 1:1 at 15 sites in Brazil. Most patients (89.3%) received glucocorticoids during hospitalization. Cumulative incidence of death or respiratory failure through day 28 was 18.1% in the tofacitinib group and 29% in the placebo group (P = 0.04). Death from any cause through Day 28 occurred in 2.8% of the patients in the tofacitinib group and in 5.5% of those in the placebo group. [199]  

Interleukin Inhibitors

Interleukin (IL) inhibitors may ameliorate severe damage to lung tissue caused by cytokine release in patients with serious COVID-19 infections. Several studies have indicated a “cytokine storm” with release of IL-6, IL-1, IL-12, and IL-18, along with tumor necrosis factor alpha (TNFα) and other inflammatory mediators. The increased pulmonary inflammatory response may result in increased alveolar-capillary gas exchange, making oxygenation difficult in patients with severe illness. 

Tocilizumab and other interleukin-6 inhibitors

IL-6 is a pleiotropic proinflammatory cytokine produced by various cell types, including lymphocytes, monocytes, and fibroblasts. SARS-CoV-2 infection induces a dose-dependent production of IL-6 from bronchial epithelial cells. This cascade of events is the rationale for studying IL-6 inhibitors. [200]  

Tocilizumab was issued an EUA on June 24, 2021 for hospitalized adults and pediatric patients (aged 2 years and older) with COVID-19 who are receiving systemic corticosteroids and require supplemental oxygen, noninvasive or invasive mechanical ventilation, or extracorporeal membrane oxygenation (ECMO). 

The Infectious Disease Society of America guidelines recommend tocilizumab in addition to standard of care (ie, steroids) among hospitalized adults with COVID-19 who have elevated markers of systemic inflammation. [28]  The NIH guidelines recommend use of tocilizumab (single IV dose of 8 mg/kg, up to 800 mg) in combination with dexamethasone in recently hospitalized patients who are exhibiting rapid respiratory decompensation caused by COVID-19. [201]  These recommendations are based on the paucity of evidence from randomized clinical trials to show certainty of mortality reduction. 

The EMPACTA trial found nonventilated hospitalized patients who received tocilizumab (n = 249) in the first 2 days of ICU admission had a lower risk for progression to mechanical ventilation or death by day 28 compared with those not treated with tocilizumab (n = 128) (12% vs 19.3%, respectively). The data cutoff for this study was September 30, 2020. In the 7 days before the trial or during the trial, 200 patients in the tocilizumab group (80.3%) and 112 patients in the placebo group (87.5%) received systemic glucocorticoids and 55.4% and 67.2% of the patients received dexamethasone. Antiviral treatment was administered in 196 (78.7%) and 101 (78.9%), respectively, and 52.6% and 58.6% received remdesivir. However, there was no difference in incidence of death from any cause between the two groups. [202]  

The REMDACTA trial did not show additional benefit for tocilizumab plus remdesivir compared with remdesivir alone in patients with severe COVID-19 pneumonia. Among 649 enrolled patients, 434 were randomly assigned to tocilizumab plus remdesivir and 215 to placebo plus remdesivir. There were 566 patients (88.2%) who also received corticosteroids during the trial to Day 28. Median time from randomization to hospital discharge was 14 days for each group. Also, there was no significant difference in deaths by Day 28 between each treatment group. [203]  

Results from the REMAP-CAP international adaptive trial evaluated efficacy of tocilizumab 8 mg/kg (n = 353), sarilumab 400 mg (n = 48), or control (n = 402) in critically ill hospitalized adults receiving organ support in intensive care. Hospital mortality at day 21 was 28% (98/350) for tocilizumab, 22.2% (10/45) for sarilumab, and 35.8% (142/397) for control. Of note, corticosteroids became part of the standard of care midway through the trial. Estimates of the treatment effect for patients treated with either tocilizumab or sarilumab and corticosteroids in combination were greater than for any single intervention. [204]   

The RECOVERY trial assessed use of 4,116 hospitalized adults with COVID-19 infection who received either tocilizumab (n = 2022) compared with standard of care (n = 2094) in the United Kingdom from April 23, 2020 to January 24, 2021. Among participants, 562 (14%) received invasive mechanical ventilation, 1686 (41%) received non-invasive respiratory support, and 1868 (45%) received no respiratory support other than oxygen. Median C-reactive protein was 143 mg/L and most patients (82% in both treatment groups) were receiving systemic corticosteroids at randomization. Tocilizumab mortality benefits were clearly seen among those who also received systemic corticosteroids. Patients in the tocilizumab group were more likely to be discharged from the hospital within 28 days (57% vs 50; p < 0.0001). Among those not receiving invasive mechanical ventilation at baseline, patients who received tocilizumab were less likely to reach the composite endpoint of invasive mechanical ventilation or death (35% vs 42%; p< 0.0001). [205]  

Conversely, the COVACTA study, 452 with COVID-19 (oxygen saturation, 93% or less) were randomly assigned in a 2:1 ratio to receive 1 dose of tocilizumab or placebo. At day 28, no significant difference was observed for mortality between the tocilizumab group and placebo (19.7% vs 19.4%, respectively). [206]   

An editorial by Rubin et al discusses the discordant results of the RECOVERY and REMAP-CAP trials compared with the COVACTA trial. One significant difference noted is that patients with severe disease, now almost universally receive glucocorticoids. Only a minority of patients in the COVACTA trial were treated with glucocorticoids. Fewer patients reeived glucocorticoids in the tocilizumab group tocilizumab (19.4%) compared with those in the placebo group (28.5%). In contrast, 93% and 82% of all patients in REMAP-CAP and the RECOVERY trial, respectively, were receiving glucocorticoid therapy. [207]  

Average wholesale price of tocilizumab is approximately $5000 for an 800-mg dose. Preliminary results for sarilumab have also been reported. 

Interleukin-1 inhibitors

Hospitalized patients with COVID-19 at increased risk for respiratory failure showed significant improvement after treatment with anakinra compared with placebo, based on data from a phase 3, randomized, confirmatory trial (SAVE-MORE study; n = 594). Patients in each study arm also received standard of care treatment. Patients were identified by increased soluble urokinase plasminogen activator receptor (suPAR) serum levels, which is an early indicator of progressing respiratory failure. At 28 days, 204 (50.4%) of the anakinra-treated patients had fully recovered, with no detectable viral RNA, compared with 50 (26.5%) of the placebo-treated patients (P< .0001). In addition, significantly fewer patients in the anakinra group had died by 28 days (13 patients, 3.2%), compared with patients in the placebo group (13 patients, 6.9%). [208]  

Endogenous IL-1 levels are elevated in individuals with COVID-19 and other conditions, such as severe CAR-T-cell–mediated cytokine-release syndrome. Anakinra has been used off-label for this indication. As of June 2020, the NIH guidelines note insufficient data to recommend for or against use of IL-1 inhibitors. [209]  

Interleukin-7 inhibitors

The recombinant interleukin-7 inhibitor, CYT107 (RevImmune), increases T-cell production and corrects immune exhaustion. Several phase 2 clinical trials have been completed in France, Belgium, and the UK to assess immune reconstitution in lymphopenic patients with COVID-19. [210, 211, 212] Phase 2 trials were initiated in November 2020 in the United States.  

Corticosteroids

The UK RECOVERY trial assessed the mortality rate at day 28 in hospitalized patients with COVID-19 who received low-dose dexamethasone 6 mg PO or IV daily for 10 days added to usual care. Patients were assigned to receive dexamethasone (n = 2104) plus usual care or usual care alone (n = 4321). Overall, 482 patients (22.9%) in the dexamethasone group and 1110 patients (25.7%) in the usual care group died within 28 days after randomization (P< 0.001). In the dexamethasone group, the incidence of death was lower than in the usual care group among patients receiving invasive mechanical ventilation (29.3% vs 41.4%) and among those receiving oxygen without invasive mechanical ventilation (23.3% vs 26.2%), but not among those who were receiving no respiratory support at randomization (17.8% vs 14%). [27]

Corticosteroids are not generally recommended for treatment of viral pneumonia. [213] The benefit of corticosteroids in septic shock results from tempering the host immune response to bacterial toxin release. The incidence of shock in patients with COVID-19 is relatively low (5% of cases). It is more likely to produce cardiogenic shock from increased work of the heart need to distribute oxygenated blood supply and thoracic pressure from ventilation. Corticosteroids can induce harm through immunosuppressant effects during the treatment of infection and have failed to provide a benefit in other viral epidemics, such as respiratory syncytial virus (RSV) infection, influenza infection, SARS, and MERS. [214]

Early guidelines for management of critically ill adults with COVID-19 specified when to use low-dose corticosteroids and when to refrain from using corticosteroids. The recommendations depended on the precise clinical situation (eg, refractory shock, mechanically ventilated patients with ARDS); however, these particular recommendations were based on evidence listed as weak. [215] The results from the RECOVERY trial in June 2020 provided evidence for clinicians to consider when low-dose corticosteroids would be beneficial. [27]

Several trials examining use of corticosteroids for COVID-19 were halted after publication of the RECOVERY trial results; however, a prospective meta-analysis from the WHO rapid evidence appraisal for COVID-19 therapies (REACT) pooled data from 7 trials (eg, RECOVERY, REMAP-CAP, CoDEX, CAP COVID) that totaled 1703 patients (678 received corticosteroids and 1025 received usual care or placebo). An association between corticosteroids and reduced mortality was similar for dexamethasone and hydrocortisone, suggesting the benefit is a general class effect of glucocorticoids. The 28-day mortality rate, the primary outcome, was significantly lower among corticosteroid users (32% absolute mortality for corticosteroids vs 40% assumed mortality for controls). [216]  An accompanying editorial addresses the unanswered questions regarding these studies. [217]   

The WHO guidelines for use of dexamethasone (6 mg IV or oral) or hydrocortisone (50 mg IV every 8 hours) for 7-10 days in the most seriously ill patients coincides with publication of the meta-analysis. [218]  

Human Vasoactive Intestinal Polypeptides

Aviptadil (Zyesami; RLF-100; NeuroRx) is a synthetic vasoactive intestinal peptide (VIP) that prevents NMDA-induced caspase-3 activation in lungs and inhibits IL-6 and TNF-alpha production. An EUA was submitted to the FDA on June 1, 2021 to treat critically ill patients with COVID-19 infection and respiratory failure. Results from a phase 2b/3 trial (COVID-AIV) of IV aviptadil for treatment of respiratory failure in critically ill patients with COVID-19 demonstrated meaningful recovery at days 28 (p = 0.014) and 60 (p = 0.013) and survival (p < 0.001). Patients enrolled in the study had respiratory failure despite prior treatment with all approved medicines for COVID-19 including remdesivir. Other therapies administered included steroids, anticoagulants, and various monoclonal antibodies.Analysis of patients who remained in respiratory failure despite treatment with remdesivir identified a statistically significant (p = .03) 2.5-fold increased odds of being alive and free of respiratory failure and a statistically significant (p = .006) fourfold higher odds of being alive at day 60 among patients treated with aviptadil compared with those treated with placebo.  Although antiviral treatment has shown advantages in treating patients with earlier stages of COVID-19, aviptadil is the first to demonstrate increased recovery and survival in patients who have already progressed to respiratory failure. [219]  

Aviptadil is being studied as part of the NIH’s ACTIV-3 critical care protocol alone and in combination with remdesivir in hospitalized patients with ARDS. 

Additionally, it is being studied as an inhaled treatment. [220]  

SYK Inhibitors 

Fostamatinib (Tavalisse; Rigel Pharmaceuticals) is a spleen tyrosine kinase (SYK) inhibitor that reduces signaling by Fc gamma receptor (FcγR) and c-type lectin receptor (CLR), which are drivers of proinflammatory cytokine release. It also reduces mucin-1 protein abundance, which is a biomarker used to predict ARDS development. It is approved in the United States for thrombocytopenia in patients with chronic immune thrombocytopenia (ITP). The active metabolite (R406) inhibits signal transduction of Fc-activating receptors and B-cell receptor to reduce antibody-mediated destruction of platelets.  

The phase 2 NIH trial randomly assigned 59 hospitalized patients (30 to fostamatinib and 29 to placebo) with COVID-19 in addition to standard of care. There were three deaths that occurred by Day 29, all receiving placebo. The mean change in ordinal score at Day 15 was greater in the fostamatinib group (-3.6 ± 0.3 vs. -2.6 ± 0.4; P = .035) and the median length in the ICU was 3 days in the fostamatinib group compared with 7 days in placebo (P = .07). Differences in clinical improvement were most evident in patients with severe or critical disease (median days on oxygen, 10 vs. 28; P = .027). [221]  

Interferons

Interferon is a natural antiviral part of the immune system. Interferon impairment is associated with the pathogenesis and severity of COVID-19 infection. The NIAID’s Adaptive COVID-19 Treatment Trial (ACTT-3) compared SC interferon beta-1a (Rebif) plus remdesivir (n = 487) with remdesivir plus placebo (n = 482) in hospitalized patients. Results showed interferon beta-1a plus remdesivir was not superior to remdesivir alone. Additionally, in patients who required high-flow oxygen at baseline, adverse effects were higher in among those receiving remdesivir plus interferon beta-1a group compared with the remdesivir plus placebo (69% vs 39%). Serious adverse events in the interferon beta-1a plus remdesivir group were also higher compared with remdesivir alone (60% vs 24%). [222]

Miscellaneous Therapies

Nitric Oxide

The Society of Critical Care Medicine recommends against the routine use of iNO in patients with COVID-19 pneumonia. Instead, they suggest a trial only in mechanically ventilated patients with severe ARDS and hypoxemia despite other rescue strategies. [215]  The cost of iNO is reported as exceeding $100/hour. 

Statins

In addition to the cholesterol-lowering abilities of HMG-CoA reductase inhibitors (statins), they also decrease the inflammatory processes of atherosclerosis. [223] Because of this, questions have arisen whether statins may be beneficial to reduce inflammation associated with COVID-19. RCTs of statins as anti-inflammatory agents for viral infections are limited, and results have been mixed.

Two meta-analyses have shown opposing conclusions regarding outcomes of patients who were taking statins at the time of COVID-19 diagnosis. [224, 225]  Randomized controlled trials are needed to examine the ability of statins to attenuate inflammation, presumably by inhibiting expression of the MYD88 gene, which is known to trigger inflammatory pathways. [226]  

Adjunctive Nutritional Therapies

NIH guidelines state there are insufficient evidence to recommend either for or against use of vitamins C and D, and zinc for treatment of COVID-19. The guidelines recommend against using zinc supplementation above the recommended dietary allowance. 

Vitamin and mineral supplements have been promoted for the treatment and prevention of respiratory viral infections; however, there is insufficient evidence to suggest a therapeutic role in treating COVID-19. [227]

Zinc

A retrospective analysis showed lack of a causal association between zinc and survival in hospitalized patients with COVID-19. [228]

Vitamin D

A study found individuals with untreated vitamin D deficiency were nearly twice as likely to test positive for COVID-19 compared with peers with adequate vitamin D levels. Among 489 individuals, vitamin D status was categorized as likely deficient for 124 participants (25%), likely sufficient for 287 (59%), and uncertain for 78 (16%). Seventy-one participants (15%) tested positive for COVID-19. In a multivariate analysis, a positive COVID-19 test was significantly more likely in those with likely vitamin D deficiency than in those with likely sufficient vitamin D levels (relative risk, 1.77; P = .02). Testing positive for COVID-19 was also associated with increasing age up to age 50 years (relative risk, 1.06; P = .02) and race other than White (relative risk, 2.54; P = .009). [229]  It is unknown if vitamin D deficiency is the specific issue, as it is also associated with various conditions that are risk factors for severe COVID-19 conditions (eg, advanced age, cardiovascular disease, diabetes mellitus). [230]  

Extended-release formulation of calcifediol (25-hydroxyvitamin D3 [Rayaldee; OPKO Health]), a prohormone of the active form of vitamin D3. Phase 2 (REsCue) completed. The objective was to raise and maintain serum total 25-hydroxyvitamin D levels to at least 25 ng/mL to mitigate COVID-19 severity in outpatients (average age 43 y; range 18-71 y). Preliminary data suggest earlier resolution of chest congestion in patients treated with 4 weeks of calcifediol compared with placebo. [231]   

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Investigational Immunotherapies

Bucillamine

Bucillamine (Revive Therapeutics) is an antirheumatic oral agent derived from tiopronin. It has been available in Japan and South Korea for over 30 years. N-acetyl-cysteine (NAC) has been shown to significantly attenuate clinical symptoms in respiratory viral infections in animals and humans, primarily via donation of thiols to increase antioxidant activity of cellular glutathione. Bucillamine has 2 thiol groups and its ability as a thiol donor is estimated to be 16 times that of NAC. A phase 3 trial for treatment of outpatients with mild-to-moderate COVID-19 at 40 sites in the United States is ongoing with an enrollment goal of 1000 participants. Interim analysis of 600-800 participants is expected in late 2021. The study was amended in late 2021 to evaluate inflammatory markers to complement in addition to viral load testing. [232]   

Other immunotherapies are in early clinical trials. 

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Investigational Antibody-Directed Therapies

Monoclonal Antibodies with EUAs

Monoclonal antibody effectiveness

Owing to the increase in variants of concern (VOC) in the United States, monoclonal antibodies that have gained emergency use authorization are continually tested to evaluate activity against VOCs. 

Data analyzed by the FDA and NIH in mid-December 2021 found tixagevimab plus cilgavimab (Evusheld) and sotrovimab retain their neutralizing activity against the omicron B.1.1.529 variant. However, casirivimab plus imdevimab (REGN-COV) and bamlanivimab plus etesevimab lost most of their effectiveness when exposed in laboratory tests to omicron B.1.1.529. [94, 95, 96]  Bebtelovimab has also shown to be effective against the omicron VOC. [233]  

Sotrovimab showed decreased efficacy against the omicron BA.2 subvariant that increased in March 2022 in the United States, prompting distribution to be paused in regions with high BA.2 prevalence and within weeks across all U.S. regions. 

Bebtelovimab

An EUA was granted by the FDA February 11, 2022 for bebtelovimab (LY-CoV1404; Eli Lilly). Bebtelovimab is a neutralizing IgG1 monoclonal antibody (mAb) directed against the spike protein of SARS-CoV-2 that maintains binding and neutralizing activity across currently known and reported variants of concern, including Omicron and BA.2. [233]    

Data supporting the EUA are primarily based on analyses from the phase 2 BLAZE-4 trial conducted before the emergence of the omicron VOC. The majority of participants were infected with the delta (49.8%) or alpha (28.6%) VOCs.  Efficacy of bebtelovimab, alone and together with bamlanivimab and etesevimab, was evaluated in low risk adults. High-risk adults and adolescents received open-label active treatments. 

Tixagevimab plus cilgavimab

An EUA was granted by the FDA in December 2021 for the long-acting antibodies (LAAB) tixagevimab plus cilgavimab (Evusheld; AstraZeneca) for use as preexposure prophylaxis COVID-19. 

Preexposure prophylaxis

The EUA was based on results from the phase 3, multicenter PROVENT trial that enrolled 5197 unvaccinated participants, of which 75% had comorbidities that placed them at increased risk for severe COVID-19. Participants were randomized 2:1 to receive a one-time dose of tixagevimab IM and cilgavimab IM (n = 3460 or saline placebo (n = 1737). In the primary efficacy analysis, risk of developing symptomatic COVID‑19 was reduced by 77% with tixagevimab plus cilgavimab compared with placebo (p < 0.001). No cases of severe COVID-19 or COVID-19–related deaths were reported in the study drug arm; in the placebo group, 1 case of severe/critical COVID-19 and 2 COVID-19–related deaths were reported. [234]  

Postexposure prophylaxis

Tixagevimab and cilgavimab are not authorized for postexposure prophylaxis of COVID-19 in individuals who have been exposed to someone infected with SARS-CoV-2. The STORM CHASER phase 3 trial did not demonstrate benefit in preventing symptomatic COVID-19 in the first 30 days. However, there was a higher proportion of symptomatic COVID-19 cases among placebo recipients after Day 29. The primary efficacy analysis compared the incidence of a participant’s first case of SARS-CoV-2 RT-PCR-positive symptomatic illness occurring post-dose and before Day 183, did not demonstrate a statistically significant effect for tixagevimab and cilgavimab compared with placebo with 23 cases of symptomatic COVID-19 in the treatment arm (3.1%) and 17 cases in the placebo arm (4.6%). [235]  

Treatment 

Tixagevimab and cilgavimab are not authorized for treatment of patients with COVID-19 disease. In the TACKLE phase 3 trial (primary analysis n = 822), outpatients with confirmed COVID-19 who had been symptomatic for 7 days or less received either tixagevimab plus cilgavimab 600 mg IM or placebo.  Tixagevimab plus cilgavimab reduced the risk of developing severe COVID-19 or death by 50% compared with placebo (18/407 vs 37/415, respectively). In those administered tixagevimab plus cilgavimab within 5 days of symptom onset, the risk was reduced by 67% compared with placebo (9/253 vs 27/251, respectively). [236]  

Monoclonal Antibodies Whose Distribution is Paused

The following monoclonal antibodies distribution have been paused in the United States owing to loss of efficacy to the omicron variants. 

Sotrovimab

Sotrovimab (VIR-7831; VIR Biotechnology; GlaxoSmithKline) is a mAb that binds to conserved epitope of the spiked protein of SARS-CoV-1 and SARS-CoV-2, thereby indicating unlikelihood of mutational escape. This is supported by a preclinical trial showing it retained ability to neutralize SARS-CoV-2 variants (ie, B.1.1.7, B.1.351, P.1). [237]  The FDA granted emergency use authorization on May 26, 2021. 

The EUA submission was based on an interim analysis of the COMET-ICE phase 3 trial.  The trial evaluated sotrovimab as monotherapy for early treatment of COVID-19 in adults at high risk of hospitalization or death. The interim analysis demonstrated an 85% reduction in hospitalization or death in those who received a single IV dose of VIR-7831 (n = 291) compared with placebo (n = 292) (p = 0.002). [238]  

Results from a phase 2 trial (BLAZE-4) of a single IV dose of VIR-7831 coadministered with bamlanivimab in low-risk adults with mild-to-moderate COVID-19 demonstrated a 70% (p < 0.001) relative reduction in persistently high viral load at day 7 compared with placebo. [239]  

IM administration

Additional trials for VIR-7831 include comparison of IM and IV administration in low-risk adults (COMET-PEAK), IM use in high-risk adults (COMET-TAIL), and IM administration in uninfected adults to prevent symptomatic infection (COMET-STAR).  

An EUA was submitted for IM administration in January 2022. The submission was based on the phase 3, randomized, open-label, COMET-TAIL trial, demonstrating that sotrovimab 500 mg IM (n = 376) was noninferior and offered similar efficacy to 500 mg IV (n=378) for early treatment of mild-to-moderate COVID-19 in high-risk, nonhospitalized adults and adolescents. Additionally, the phase 2 COMET-PEAK trial confirmed equivalent virological response between IM and IV administration. [240]   

Casirivimab plus imdevimab

An EUA was issued for intravenous coadministration of the monoclonal antibodies casirivimab and imdevimab (REGN-COV; Regeneron) on November 21, 2020 for treatment of mild-to-moderate COVID-19 in adults and pediatric patients aged 12 years and older who weigh at least 40 kg and are at high risk for progressing to severe COVID-19 and/or hospitalization. [241]  The mixture is designed to bind to 2 points on the SARS-CoV-2 spike protein. As with bamlanivimab, administration of casirivimab and imdevimab has not shown benefit in hospitalized patients with severe COVID-19. 

In June 2021, the EUA was updated with a lower recommended IV dose of casirivimab 600 mg and imdevimab 600 mg. This update also allowed for administration as a SC injection when an IV infusion is not feasible. 

In July 2021, the EUA updated to include use as postexposure prophylaxis for individuals at high risk of progression to severe COVID-19, including hospitalization or death, and are not fully vaccinated or are not expected to mount an adequate immune response. [242]

Treatment trials

Intravenous casirivimab and imdevimab reduced viral levels and improved symptoms in nearly 800 non-hospitalized patients with COVID-19 disease in a phase 2/3 trial. Results showed treatment with the 2 antibodies reduced COVID-19 related medical visits by 57% through day 29 (2.8% combined dose groups; 6.5% placebo; p = 0.024). In high risk patients (1 or more risk factor including age older than 50 years; body mass index greater than 30; cardiovascular, metabolic, lung, liver or kidney disease; or immunocompromised status) COVID-19 related medical visits were reduced by 72% (p = 0.0065). [243, 244]  

A phase 3 trial (n = 4,567) in infected outpatients who were at high risk for hospitalization or severe COVID-19 disease found casirivimab plus imdevimab significantly reduced the risk of hospitalization or death. Risk was decreased by 70% with the 1200 mg IV dose (n = 827) and by 71% with 2400 mg IV (n = 1,849) compared with placebo (n = 1,843). [245]   

A phase 3 trial showed casirivimab plus imdevimab significantly reduced viral load within 7 days of treatment in seronegative patients hospitalized with COVID-19 who did not require high-flow oxygen or mechanical ventilation at baseline. Risk of death or mechanical ventilation decreased by approximately 50% after 1 week following treatment with the antibody cocktail. Seronegative patients (n = 217) had much higher viral loads than those who had already developed their own antibodies (seropositive [n = 270]) to SARS-CoV-2 at the time of randomization. In seronegative patients, the antibody cocktail reduced the time-weighted average daily viral load through day 7 by -0.54 log10 copies/mL, and through day 11 by -0.63 log10 copies/mL (nominal p = 0.002 for combined doses). As expected, the clinical and virologic benefit of the antibody cocktail was limited in seropositive patients. [246, 247]  

The much larger UK-based RECOVERY trial showed reduced 28-day mortality among hospital patients who were seronegative at baseline for antibodies. Between September 18, 2020 and May 22, 2021, 9785 patients were randomly allocated to receive usual care plus casirivimab/imdevimab or usual care alone, including 3153 (32%) seronegative patients, 5272 (54%) seropositive patients, and 1360 (14%) patients with unknown baseline antibody status. In the primary efficacy population of seronegative patients, 396 (24%) of 1633 patients allocated to casirivimab/imdevimab and 451 (30%) of 1520 patients allocated to usual care died within 28 days (p = 0.001). In an analysis involving all randomized patients (regardless of baseline antibody status), 944 (20%) of 4839 patients allocated to casirivimab/imdevimab and 1026 (21%) of 4946 patients allocated to usual care died within 28 days (p = 0.17). The proportional effect of mortality differed significantly between seropositive and seronegative patients for those who received the monoclonal antibody combination (p = 0.001). [248]

Prevention trials

A phase 3 trial showed risk reduction of symptomatic SARS-CoV-2 infection of household contacts administered casirivimab and imdevimab following exposure through day 29 (relative risk reduction, 81.4%; p < 0.001). Participants received either a single 1,200-mg SC dose of casirivimab and imdevimab (n = 753) or placebo (n=752) within 96 hours following exposure. Risk of symptomatic infection was decreased by 71.9% in the first week, and 92.6% in subsequent weeks. Among individuals who developed symptomatic infections, those who received casirivimab and imdevimab cleared the virus faster and had a shorter duration of symptoms compared with placebo. [242]  

Bamlanivimab plus etesevimab 

Bamlanivimab and etesevimab (LY-CoV555; Eli Lilly & Co, AbCellera) are neutralizing IgG1 monoclonal antibodies (mAb) directed against the spike protein of SARS-CoV-2 designed to block viral attachment and entry into human cells, thus neutralizing the virus, potentially preventing and treating COVID-19. Emergency use authorization of bamlanivimab and etesevimab is for treatment of mild-to-moderate COVID-19 in adults and children, including neonates, with positive results of direct SARS-CoV-2 viral testing, and who are at high risk for progression to severe COVID-19, including hospitalization or death. 

Treatment trials

The EUA for treatment was based on results from the phase 3 BLAZE-1 trial. A total of 1035 patients underwent randomization and received an IV infusion of bamlanivimab plus etesevimab or placebo. By day 29, a total of 11 of 518 patients (2.1%) in the bamlanivimab plus etesevimab group had a COVID-19–related hospitalization or death from any cause, compared with 36 of 517 patients (7%) in the placebo group (P < 0.001). No deaths occurred in the bamlanivimab plus etesevimab group. Ten deaths occurred in the placebo group, 9 of which were designated by the trial investigators as COVID-1919–related. At day 7, a greater reduction from baseline in the log viral load was observed among patients who received bamlanivimab plus etesevimab than among those who received placebo (P < 0.001). [249]   

Postexposure prophylaxis

The EUA for bamlanivimab plus etesevimab was updated to include postexposure prophylaxis in certain individuals on September 16, 2021. Specifically, postexposure prophylaxis is indicated for patients aged 12 years and older and weigh at least 40 kg who are:

  • at high risk for progression to severe COVID-19 and are not fully vaccinated or 
  • who are not expected to mount an adequate immune response to complete SARS-CoV-2 vaccination and have been exposed to an infected individual or at high risk of exposure to an infected individual (eg, nursing home) 

Inclusion of this indication in the EUA was based on the BLAZE-2 phase 3 trial that enrolled residents and staff of 74 skilled nursing and assisted living facilities in the United States with at least 1 confirmed SARS-CoV-2 index case from August 2 to November 20, 2020. Participants were randomized to receive a single IV infusion of bamlanivimab, 4200 mg (n = 588), or placebo (n = 587). Bamlanivimab significantly reduced the incidence of COVID-19 in the prevention population compared with placebo (8.5% vs 15.2%; P < 0.001). Five deaths attributed to COVID-19 were reported by day 57; all occurred in the placebo group. [250]   

Other Monoclonal Antibodies Pending EUA

Amubarvimab/romlusevimab

An EUA was submitted to the FDA in early October 2021 for amubarvimab/romlusevimab (BRII-196/BRII-198; Brii Biosciences Ltd) to reduce the risk of hospitalization and death in individuals with COVID-19. Amubarvimab/romlusevimab were specifically engineered to reduce the risk of antibody-dependent enhancement and prolong the plasma half-lives for potentially more durable treatment effect. Their non-overlapping epitope binding regions provide a high degree of neutralization activity against SARS-CoV-2.

Phase 3 results from the NIH ACTIV-2 trial of outpatients with mild COVID-19 treated with amubarvimab/romlusevimab demonstrated a 78% reduction in relative risk as measured by hospitalizations or death compared with placebo (p < 0.00001). Among patients who received treatment with amubarvimab/romlusevimab within 5 days of symptom onset, 2% (4/196) progressed to hospitalization or death, compared with 11% (21/197) in the placebo arm. Similarly, 2% (5/222) of subjects who received treatment with amubarvimab/romlusevimab at 6-10 days following symptom onset progressed to hospitalization or death, compared with 11% (24/222) of those receiving placebo. The analysis also showed no deaths in the treatment arm versus 8 deaths in the placebo arm through day 28. There was1 death in each arm during the post 28-day follow up. [251]  

Adintrevimab

Adintrevimab (ADG20; Adagio Therapeutics) it a long-acting mAb that elicits high potency and broad neutralization against SARS-CoV-2 and additional clade 1 sarbecoviruses, by targeting a highly conserved CR3022 epitope in the receptor binding domain.

Preliminary data from the phase 2/3 trials for preexposure prophylaxis (EVADE) and treatment (STAMP) showed risk of symptomatic COVID-19 was reduced by 71% and 75% compared with placebo respectively. It is administered as a single IM injection in the upper thigh. [252, 253]  

Convalescent Plasma

An expanded access (EA) program for convalescent plasma was initiated in early April 2020. [137] The FDA granted emergency use authorization (EUA) on August 23, 2020 for use of convalescent plasma in hospitalized patients with COVID-19. [254] Convalescent plasma contains antibody-rich plasma products collected from eligible donors who have recovered from COVID-19. Clinical trial results have been disappointing with early use in high-risk outpatients, [255]  and also in hospitalized patients with advanced disease. [256]  Very early use in nursing home settings continue to be investigated. 

The NIH halted its trial of convalescent plasma in emergency departments for treatment of high-risk outpatients with mild symptoms as of March 2021 after interim results showed use with 1 week after symptom onset did not prevent disease progression. Final results of the SIREN-C3PO trial (n= 511) showed disease progression occurred in 77/257 patients (30%) in the convalescent-plasma group and in 81/254 patients (31.9%) in the placebo group. [255]  

The REMAP-CAP investigators concluded that among critically ill adults with confirmed COVID-19, treatment with 2 units of high-titer, ABO-compatible convalescent plasma had a low likelihood of providing improvement in the number of organ support–free days. The study’s primary end point was organ support–free days (days alive and free of intensive care unit–based organ support) up to day 21. Among 2011 participants who were randomized, 1990 (99%) completed the trial. The convalescent plasma intervention was stopped after the prespecified criterion for futility was met. Median number of organ support–free days was 0 in the convalescent plasma group and 3 in the no convalescent plasma group. The in-hospital mortality rate was 37.3% (401/1075) for the convalescent plasma group and 38.4% (347/904) for the no convalescent plasma group and the median number of days alive and free of organ support was 14 for each group. [256]    

NIH and IDSA guidelines [28, 257]  continue to be updated as evidence from randomized, controlled trials emerge. 

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Vaccines

mRNA vaccine (Comirnaty; Pfizer) and mRNA-1273 (Spikevax; Moderna) have gained full FDA approval. Another SARS-CoV-2 vaccine available in the United States through emergency use authorization is a viral vector vaccine – Ad26.COV2.S (Johnson & Johnson). For full discussion regarding vaccines, see COVID-19 Vaccines

The genetic sequence of SARS-CoV-2 was published on January 11, 2020. The rapid emergence of research and collaboration among scientists and biopharmaceutical manufacturers followed. Various methods are used for vaccine discovery and manufacturing. 

In addition to the complexity of finding the most effective vaccine candidates, the production process is also important for manufacturing the vaccine to the scale needed globally. Other variable that increase complexity of distribution include storage requirements (eg, frozen vs refrigerated) and if more than a single injection is required for optimal immunity. Several technological methods (eg, DNA, RNA, inactivated, viral vector, protein subunit) are available for vaccine development. Vaccine attributes (eg, number of doses, speed of development, scalability) depends on the type of technological method employed. For example, the mRNA vaccine platforms allow for rapid development. [258, 259]

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Antithrombotics

COVID-19 is a systemic illness that adversely affects various organ systems. A review of COVID-19 hypercoagulopathy aptly describes both microangiopathy and local thrombus formation, and a systemic coagulation defect leading to large vessel thrombosis and major thromboembolic complications, including pulmonary embolism, in critically ill patients. [260]  While sepsis is recognized to activate the coagulation system, the precise mechanism by which COVID-19 inflammation affects coagulopathy is not fully understood. [261]   

Several retrospective cohort studies have described use of therapeutic and prophylactic anticoagulant doses in critically ill hospitalized patients with COVID-19. No difference in 28-day mortality was observed for 46 patients empirically treated with therapeutic anticoagulant doses compared with 95 patients who received standard DVT prophylaxis doses, including those with D-dimer levels greater than 2 mcg/mL. In this study, day 0 was the day of intubation, therefore, they did not evaluate all patients who received empiric therapeutic anticoagulation at the time of diagnosis to see if progression to intubation was improved. [262]  

In contrast to the above findings, a retrospective cohort study showed a median 21 day survival for patients requiring mechanical ventilation who received therapeutic anticoagulation compared with 9 days for those who received DVT prophylaxis. [263]   

NIH Trial

Guidelines include thrombosis prophylaxis (typically with low-molecular-weight heparin [LMWH]) for hospitalized patients. The NIH ACTIV trial includes an arm (ACTIV-4) for use of antithrombotics in the outpatient (trial closed as of June 2021), inpatient, and convalescent settings. 

The three adaptive clinical trials within ACTIV-4 include preventing, treating, and addressing COVID-19-associated coagulopathy (CAC). Additionally, a goal to understand the effects of CAC across patient populations – inpatient, outpatient, and convalescent. 

Outpatient trial 

For nonhospitalized patients with COVID-19, anticoagulants and antiplatelet therapy should not be initiated for the prevention of VTE or arterial thrombosis unless the patient has other indications for the therapy or is participating in a clinical trial.

The ACTIV-4B was initiated mid-2020 to investigate whether anticoagulants or antithrombotic therapy can reduce life-threatening cardiovascular or pulmonary complications in newly diagnosed patients with COVID-19 who do not require hospital admission. Participants were randomized to take either a placebo, aspirin, or a low or therapeutic dose of apixaban. The outpatient thrombosis prevention study was halted as the researchers concluded that among mildly symptomatic but clinically stable COVID-19 outpatients a week or more since the time of diagnosis, rates of major cardio-pulmonary complications are very low and do not justify preventive anticoagulant or antiplatelet therapy unless otherwise clinically indicated. [264]   

Inpatient trial 

Investigates an approach aimed at preventing clotting events and improving outcomes in hospitalized patients with COVID-19. Results published in August 2021 found full-dose anticoagulation (ie, therapeutic dose parenteral anticoagulation with SC low-molecular weight heparin [LMWH] or IV unfractionated heparin) reduced the need for organ support in moderately ill hospitalized patients (n = 2,219), but not in critically ill patients (n = 1,098). Additionally, full dose anticoagulation in critically ill patients, and may cause harm compared with those give usual-care thromboprophylaxis (ie, thromboprophylactic dose anticoagulation according to local practice). Among moderately ill patients, researchers found that the likelihood of full-dose heparin to reduce the need for organ support compared to those who received low-dose heparin was 98.6%. To ensure adequate separation between the study groups the dose of heparin/LMWH used in the usual care arm did not equal more than half of the approved therapeutic dose for that agent for the treatment of venous thromboembolism. These results emphasize the need to stratify patients with different disease severity within clinical trials. [265, 266]  

Convalescent trial

Investigates safety and efficacy apixaban administered to patients who have been discharged from the hospital or are convalescing in reducing thrombotic complications (eg, MI, stroke, DVT, PE, death). Patients will be assessed for these complications within 45 days of being hospitalized for moderate and severe COVID-19.

Investigational antithrombotics

AB201

AB201 (ARCA Biopharma) is a recombinant nematode anticoagulant protein c2 (rNAPc2) that specifically inhibits tissue factor (TF)/factor VIIa complex and has anticoagulant, anti-inflammatory, and potential antiviral properties. TF plays a central role in inflammatory response to viral infections. The phase 2b/3 clinical trial (ASPEN-COVID-19) completed enrollment (n = 160). The trial randomized 2 AB201 dosage regimens compared with heparin in hospitalized SARS-CoV-2 positive patients with an elevated D-dimer level. The primary endpoint was change in D-dimer level from baseline to Day 8. The phase 3 trial design is contingent upon phase 2b results. [267]  

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Renin Angiotensin System Blockade and COVID-19

SARS-CoV-2 is known to utilize angiotensin-converting enzyme 2 (ACE2) receptors for entry into target cells. [268] Data are limited concerning whether to continue or discontinue drugs that inhibit the renin-angiotensin-aldosterone system (RAAS), namely angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs). 

The first randomized study to compare continuing vs stopping (ACEIs) or ARBs receptor for patients with COVID-19 has shown no difference in key outcomes between the 2 approaches. A similar 30-day mortality rate was observed for patients who continued and those who suspended ACE inhibitor/ARB therapy, at 2.8% and 2.7%, respectively (hazard ratio, 0.97). [269]  

The BRACE Corona trial design further explains the 2 hypotheses. [269]  

  • One hypothesis suggests that use of these drugs could be harmful by increasing the expression of ACE2 receptors (which the SARS-CoV-2 virus uses to gain entry into cells), thus potentially enhancing viral binding and viral entry.
  • The other suggests that ACE inhibitors and ARBs could be protective by reducing production of angiotensin II and enhancing the generation of angiotensin 1-7, which attenuates inflammation and fibrosis and therefore could attenuate lung injury. 

Concern arose regarding appropriateness of continuation of ACEIs and ARBs in patients with COVID-19 after early reports noted an association between disease severity and comorbidities such as hypertension, cardiovascular disease, and diabetes, which are often treated with ACEIs and ARBs. The reason for this association remains unclear. [270, 271]

The speculated mechanism for detrimental effect of ACEIs and ARBs is related to ACE2. It was therefore hypothesized that any agent that increases expression of ACE2 could potentially increase susceptibility to severe COVID-19 by improving viral cellular entry; [271] however, physiologically, ACE2 also converts angiotensin 2 to angiotensin 1-7, which leads to vasodilation and may protect against lung injury by lowering angiotensin 2 receptor binding. [270, 272] It is therefore uncertain whether an increased expression of ACE2 receptors would worsen or mitigate the effects of SARS-CoV-2 in human lungs.

Vaduganathan and colleagues note that data in humans are limited, so it is difficult to support or negate the opposing theories regarding RAAS inhibitors. They offer an alternate hypothesis that ACE2 may be beneficial rather than harmful in patients with lung injury. As mentioned, ACE2 acts as a counterregulatory enzyme that degrades angiotensin 2 to angiotensin 1-7. SARS-CoV-2 not only appears to gain initial entry through ACE2 but also down-regulates ACE2 expression, possibly mitigating the counterregulatory effects of ACE2. [273]

There are also conflicting data regarding whether ACEIs and ARBs increase ACE2 levels. Some studies in animals have suggested that ACEIs and ARBs increase expression of ACE2, [274, 275, 276] while other studies have not shown this effect. [277, 278]

As uncertainty remains regarding whether ACEIs and/or ARBs increase ACE2 expression and how this effect may influence outcomes in patients with COVID-19, cardiology societies have largely recommended against initiating or discontinuing these medications based solely on active SARS-CoV-2 infection. [279, 280]  

A systematic review and meta-analysis found use of ACEIs or ARBs was not associated with a higher risk of mortality among patients with COVID-19 with hypertension or multiple comorbidities, supporting recommendations of medical societies to continue use of these agents to control underlying conditions. [281]  

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Diabetes and COVID-19

High plasma glucose levels and diabetes mellitus (DM) are known risk factors for pneumonia. [282, 283] Potential mechanisms that may increase the susceptibility for COVID-19 in patients with DM include the following [284] :

  • Higher-affinity cellular binding and efficient virus entry
  • Decreased viral clearance
  • Diminished T-cell function
  • Increased susceptibility to hyperinflammation and cytokine storm syndrome
  • Presence of cardiovascular disease

SARS-CoV-2 is known to utilize angiotensin-converting enzyme 2 (ACE2) receptors for entry into target cells. Insulin administration attenuates ACE2 expression, while hypoglycemic agents (eg, glucagonlike peptide 1 [GLP-1] agonists, thiazolidinediones) up-regulate ACE2. [284] Dipeptidyl peptidase 4 (DPP-4) is highly involved in glucose and insulin metabolism, as well as in immune regulation. This protein was shown to be a functional receptor for Middle East respiratory syndrome coronavirus (MERS-CoV), and protein modeling suggests that it may play a similar role with SARS-CoV-2, the virus responsible for COVID-19. [285]

The relationship between diabetes, coronavirus infections, ACE2, and DPP-4 has been reviewed by Drucker. [283] Important clinical conclusions of the review include the following:

  • Hospitalization is more common for acute COVID-19 among patients with diabetes and obesity.
  • Diabetic medications need to be reevaluated upon admission.
  • Insulin is the glucose-lowering therapy of choice, not DPP-4 inhibitors or GLP-1 receptor agonists, in patients with diabetes who are hospitalized with acute COVID-19.
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Therapies Determined Ineffective

Hydroxychloroquine or chloroquine

The EUA for treatment of COVID-19 with hydroxychloroquine or chlorquine was issued by the FDA in March 2020 and subsequently revoked in June 2020 owing to safety concerns and lack of efficacy. 

Additionally, the NIH halted the Outcomes Related to COVID-19 treated with Hydroxychloroquine among In-patients with symptomatic Disease (ORCHID) study on June 20, 2020. After the fourth analysis that included more than 470 participants, the NIH data and safety monitoring board determined that, while there was no harm, the study drug was very unlikely to be beneficial to hospitalized patients with COVID-19.

The NIH COVID-19 Treatment Guidelines recommends against the use of chloroquine or hydroxychloroquine and/or azithromycin for the treatment of COVID-19 in hospitalized patients and in nonhospitalized patients. 

Doxycycline

A few case reports and small case series have speculated on a use for doxycycline in COVID-19. Most seem to have been searching for an antibacterial to replace azithromycin for use in combination with hydroxychloroquine. In general, the use of HCQ has been abandoned. The anti-inflammatory effects of doxycycline were also postulated to moderate the cytokine surge of COVID-19 and provide some benefits. However, the data on corticosteroid use has returned, and is convincing and strongly suggests their use. It is unclear that doxycycline would provide further benefits. Finally, concomitant bacterial infection during acute COVID-19 is proving to be rare decreasing the utility of antibacterial drugs. Overall, there does not appear to be a routine role for doxycycline.

Lopinavir/ritonavir

The NIH Panel for COVID-19 Treatment Guidelines recommend against the use of lopinavir/ritonavir or other HIV protease inhibitors, owing to unfavorable pharmacodynamics and because clinical trials have not demonstrated a clinical benefit in patients with COVID-19.

The Infectious Diseases Society of America (IDSA) guidelines recommend against the use of lopinavir/ritonavir. The guidelines also mention the risk for severe cutaneous reactions, QT prolongation, and the potential for drug interactions owing to CYP3A inhibition. [28]

The RECOVERY trial concluded no beneficial effect was observed in hospitalized patients with COVID-19 who were randomized to receive lopinavir/ritonavir (n = 1616) compared with those who received standard care (n = 3424). No significant difference for 28-day mortality was shown. Overall, 374 (23%) patients allocated to lopinavir/ritonavir and 767 (22%) patients allocated to usual care died within 28 days (P = 0.60). No evidence was found for beneficial effects on the risk of progression to mechanical ventilation or length of hospital stay. [286]

The WHO discontinued use of lopinavir/ritonavir in the SOLIDARITY trial in hospitalized patients on July 4, 2020. [141]  Interim results released mid-October 2020 found lopinavir/ritonavir (with or without interferon) appeared to have little or no effect on hospitalized patients with COVID-19, as indicated by overall mortality, initiation of ventilation, and duration of hospital stay. Death rate ratios were: lopinavir, 1.00 (P = 0.97; 148/1399 vs 146/1372) and lopinavir plus interferon, 1.16 (P = 0.11; 243/2050 vs 216/2050). [142]  

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QT Prolongation with Potential COVID-19 Pharmacotherapies

Chloroquine, hydroxychloroquine, and azithromycin each carry the warning of QT prolongation and can be associated with an increased risk of cardiac death when used in a broader population. [287] Because of this risk, the American College of Cardiology, American Heart Association, and the Heart Rhythm Society have published a thorough discussion on the arrhythmogenicity of hydroxychloroquine and azithromycin, including a suggested protocol for clinical research QT assessment and monitoring when the two drugs are coadministered. [288, 289]

Giudicessi and colleagues [290] have published guidance for evaluating the torsadogenic potential of chloroquine, hydroxychloroquine, lopinavir/ritonavir, and azithromycin. Chloroquine and hydroxychloroquine block the potassium channel, specifically KCNH2-encoded HERG/Kv11.1. Additional modifiable risk factors (eg, treatment duration, other QT-prolonging drugs, hypocalcemia, hypokalemia, hypomagnesemia) and nonmodifiable risk factors (eg, acute coronary syndrome, renal failure, congenital long QT syndrome, hypoglycemia, female sex, age ≥65 years) for QT prolongation may further increase the risk. Some of the modifiable and nonmodifiable risk factors may be caused by or exacerbated by severe illness. 

A cohort study was performed from March 1 through April 7, 2020, to characterize the risk and degree of QT prolongation in patients with COVID-19 who received hydroxychloroquine, with or without azithromycin. Among 90 patients given hydroxychloroquine, 53 received concomitant azithromycin. Seven patients (19%) who received hydroxychloroquine monotherapy developed prolonged QTc of 500 milliseconds or more, and 3 patients (3%) had a change in QTc of 60 milliseconds or more. Of those who received concomitant azithromycin, 11 of 53 (21%) had prolonged QTc of 500 milliseconds or more, and 7 of 53 (13 %) had a change in QTc of 60 milliseconds or more. Clinicians should carefully monitor QTc and concomitant medication usage if considering using hydroxychloroquine. [291]

A retrospective study reviewed 84 consecutive adult patients hospitalized with COVID-19 and treated with hydroxychloroquine plus azithromycin. The QTc increased by greater than 40 ms in 30% of patients. In 11% of patients, QTc increased to more than 500 ms, which is considered a high risk for arrhythmia. The researcher noted that development of acute renal failure, but not baseline QTc, was a strong predictor of extreme QTc prolongation. [292]

A Brazilian study (n=81) compared chloroquine high-dose (600 mg PO BID for 10 days) and low-dose (450 mg BID for 1 day, then 450 mg/day for 4 days). A positive COVID-19 infection was confirmed by RT-PCR in 40 of 81 patients. In addition, all patients received ceftriaxone and azithromycin. Oseltamivir was also prescribed in 89% of patients. Prolonged QT interval (> 500 msec) was observed in 25% of the high-dose group, along with a trend toward higher lethality (17%) compared with lower dose. this prompted the investigators to prematurely halt use of the high-dose treatment arm, noting that azithromycin and oseltamivir can also contribute to prolonged QT interval. The fatality rate was 13.5%. In 14 patients with paired samples, respiratory secretions at day 4 showed negative results in only one patient. [293]

An increased 30-day risk of cardiovascular mortality, chest pain/angina, and heart failure was observed with the addition of azithromycin to hydroxychloroquine. Pooled data from 14 sources of claims data or electronic medical records from Germany, Japan, Netherlands, Spain, United Kingdom, and the United States were analyzed for adverse effects of hydroxychloroquine, sulfasalazine, or the combinations of hydroxychloroquine plus azithromycin or amoxicillin. Overall, 956,374 and 310,350 users of hydroxychloroquine and sulfasalazine, respectively, and 323,122 and 351,956 users of hydroxychloroquine-azithromycin and hydroxychloroquine-amoxicillin, respectively, were included in the analysis. [294]

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Investigational Devices

Blood purification devices

Several extracorporeal blood purification filters (eg, CytoSorb, oXiris, Seraph 100 Microbind, Spectra Optia Apheresis) have received emergency use authorization from the FDA for the treatment of severe COVID-19 pneumonia in patients with respiratory failure. The devices have various purposes, including use in continuous renal replacement therapy or in reduction of proinflammatory cytokines levels. [295]  

Nanosponges

Cellular nanosponges made from plasma membranes derived from human lung epithelial type II cells or human macrophages have been evaluated in vitro. The nanosponges display the same protein receptors required by SARS-CoV-2 for cellular entry and act as decoys to bind the virus. In addition, acute toxicity was evaluated in vivo in mice by intratracheal administration. [296]   

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