COVID-19 Treatment: Investigational Drugs and Other Therapies

Coronavirus disease 2019 (COVID-19) is defined as illness caused by a novel coronavirus now called severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2; formerly called 2019-nCoV), which was first identified amid an outbreak of respiratory illness cases in Wuhan City, Hubei Province, China. ^[1] It initially was reported to the WHO on December 31, 2019. On January 30, 2020, the WHO declared the COVID-19 outbreak a global health emergency. ^{[2, 3]} On March 11, 2020, the WHO declared COVID-19 a global pandemic, its first such designation since declaring H1N1 influenza a pandemic in 2009. ^[4]   

On May 11, 2023, the federal COVID-19 public health emergency (PHE) ended; however, COVID-19 continues to be a health risk. ^[5]   

Programs established by the FDA allowing clinicians to gain access to investigational therapies during the pandemic have 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 of providing medical countermeasures in the event of infectious disease and other threats. ^[6]   

EUA fact sheets for clinicians are available to provide detailed information regarding drugs, biologicals, and vaccines that have been issued an EUA as a COVID-19 therapy or prevention. 

Investigational Integrity

Numerous other antiviral agents, immunotherapies, and vaccines continue to be investigated and developed as potential therapies. Searching for effective therapies for COVID-19 infection is a complex process. Guidelines for COVID-19 have been published and continue to be revised as evidence emerges. ^{[7, 8]}  The Milken Institute maintains a detailed COVID-19 Treatment and Vaccine Tracker of research and development progress. 

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. ^[9]

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. ^[10]  

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. ^[11]  

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.

Another adaptive platform trial is the I-SPY COVID-19 Trial for treating critically ill patients. The clinical trial is designed to allow numerous investigational agents to be evaluated in the span of 4 to 6 months, compared with standard of care (supportive care for ARDS, remdesivir backbone therapy). As the trial proceeds and a better understanding of the underlying mechanisms of the COVID-19 illness emerges, expanded biomarker and data collection can be added as needed to further elucidate how agents are or are not working. ^[12]

The WHO developed a blueprint of potential therapeutic candidates in January 2020. WHO embarked on an ambitious global "megatrial" called SOLIDARITY in which confirmed cases of COVD-19 are randomized 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. ^[13]  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). ^[14]  

The next phase of the trial, Solidarity PLUS, continued in August 2021. WHO announced over 600 hospitals in 52 countries participated in testing three drugs (ie, artesunate, imatinib, infliximab). Patients were randomized to standard of care (SOC) or SOC plus one of the study drugs.

Remdesivir

Remdesivir (Veklury; Gilead) was the first drug approved by the FDA  to treat the SARS-CoV-2 virus. It is indicated for treatment of COVID-19 disease in adults and children (birth to < 18 years of age weighing at least 1.5 kg) who are hospitalized, or not hospitalized and have mild-to-moderate COVID-19 and are at high risk for progression to severe COVID-19, including hospitalization or death. 

The broad-spectrum antiviral is a nucleotide analog prodrug. Full approval was preceded by the US FDA issuing an EUA (emergency use authorization) on May 1, 2020 to allow prescribing of remdesivir for severe COVID-19 (confirmed or suspected) in hospitalized adults and children prior to approval. ^[15]   

Inpatient remdesivir

Several phase 3 clinical trials have tested remdesivir for treatment of COVID-19 in the United States, South Korea, and China. 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. ^[16]  An adaptive randomized trial of remdesivir coordinated by the National Institutes of Health (NCT04280705) was started first against placebo, but additional therapies have been added to the protocol as evidence emerges. 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. ^[17] Trials of remdesivir for moderate and severe COVID-19 compared with standard of care and varying treatment durations are ongoing.

The 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 recovered faster than similar patients who received placebo. Results showed that patients who received remdesivir had a 31% faster time to recovery compared with those who received placebo (P < 0.001). Specifically, the median time to recovery was 10 days in patients treated with remdesivir compared with 15 days in those who received placebo (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%). ^[18]

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. In SOLIDARITY, over 11,000 hospitalized patients with COVID-19 (from 405 hospitals and 30 countries) were randomized between whichever study drugs (up to four options) were locally available and open control. ^[14] An analysis by Sax describes variables to consider when interpreting the results.

The ACTT-1 trial included a placebo arm and was blinded, providing stronger evidence of remdesivir efficacy. Also, remdesivir worked for patients with shorter duration of symptoms and in those requiring oxygen. When the SOLIDARITY trial began in March 2020, it was a time during much of the enrollment period when patients tried to avoid hospitalization. When the drug was initiated in relation to the stage of infection is an important factor. Duration of symptoms is not reported in the preliminary SOLIDARITY trial, a critical piece of information. ^[19]  

An editorial by Harrington et al 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 editorial also mentions 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. ^[20]  

Similar to the SOLIDARITY trial, the DisCoVeRy open-label, multicenter trial did not show clinical benefit from use of remdesivir. The trial was conducted in 48 sites 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 two 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. ^[21]  

The ACTT results also differed from a smaller randomized trial conducted in China and published hours before the press release by the NIH about the study. Results from this other randomized, double-blind, placebo-controlled, multicenter trial (n = 237; 158 to remdesivir and 79 to placebo; 1 patient withdrew) found remdesivir was not associated with statistically significant clinical benefits, measured as time to clinical improvement, in adults hospitalized with severe COVID-19. Although not statistically significant, patients receiving remdesivir had a numerically faster time to clinical improvement than those receiving placebo among patients with symptom duration of 10 days or less. The authors concluded that numerical reduction in time to clinical improvement in those treated earlier requires confirmation in larger studies. This study was underpowered owing to dropping case numbers in China as the study was starting. ^[22]

A phase 3, randomized, open-label trial showed remdesivir was associated with significantly greater recovery and reduced odds of death compared with standard of care in patients with severe COVID-19. The recovery rate at day 14 was higher in patients who received remdesivir (n = 312) compared with those who received standard of care (n = 818) (74.4% vs 59%; P < 0.001). The mortality rate at day 14 also was lower in the remdesivir group (7.6% vs 12.5%; P = 0.001). ^[23]

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 [OR], 0.75). In this study, 65% of patients who received a 5-day course of remdesivir showed a clinical improvement of at least 2 points on the 7-point ordinal scale at day 14, compared with 54% of patients who received a 10-day course. 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 study demonstrates the potential for some patients to be treated with a 5-day regimen, which 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. ^[24]

Data presented at the virtual COVID-19 Conference in July 2020 included a comparative analysis of clinical recovery and mortality outcomes from the phase 3 SIMPLE trials versus a real-world cohort of patients with severe COVID-19 receiving standard of care. The analysis showed remdesivir was associated with a 62% reduction in the risk for mortality compared with standard of care. Subgroup analyses found these results were similar across different racial and ethnic groups. Although these data are important, they require confirmation in prospective clinical trials. ^[25]

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). ^[26]  

Real-world analysis

Three retrospective real-world studies presented at the 30th Conference on Retroviruses and Opportunistic Infections (CROI) 2023 showed when remdesivir was initiated within the first 2 days of hospital admission, patients had significantly lower risk for mortality and hospital readmission compared with matched controls. The studies included more than 500,000. ^[27]

Two studies analyzed clinical practice information from the US Premier Healthcare databases of more than 500,000 adult patients hospitalized with COVID-19. The overall analysis examined all-cause inpatient mortality rates at 14- and 28- days and demonstrated that initiation of remdesivir within the first 2 days of hospital admission was associated with a statistically significant lower risk for mortality in all oxygen levels compared with matched controls that did not receive remdesivir during their hospitalization. For patients with no documented use of supplemental oxygen at baseline, treatment with remdesivir was associated with a 19% (p < 0.001) lower risk for mortality at day 28. Patients on low-flow or high-flow oxygen also had a 21% (p < 0.001) and 12% (p < 0.001) lower risk for mortality at day 28, respectively. Patients on invasive mechanical ventilation/ECMO at baseline had a 26% (p < 0.001) reduced risk for mortality at day 28. 

The second analysis demonstrated that a reduction in mortality also was associated in vulnerable patient populations (eg, patients with immunocompromised conditions, who can experience repeat infections and breakthrough infections). Results demonstrated that at day 28 mortality results showed that timely initiation of remdesivir treatment within 2 days of hospital admission was associated with an overall 25% significantly lower risk compared with non-remdesivir across all variant time periods, ie, pre-Delta (35%), Delta (21%), and Omicron (16%). 

A meta-analysis showed remdesivir reduced mortality in patients hospitalised with COVID-19 who required no or conventional oxygen support, but was underpowered to evaluate patients who were ventilated when receiving remdesivir. ^[28]  

Remdesivir use in children

As of February 2024, remdesivir has full FDA approval for children of all ages, including at birth. 

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. ^[29]

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. ^[30]

For additional information, see Coronavirus Disease 2019 (COVID-19) in Children.

Remdesivir use in pregnant women

Outcomes in the first 86 pregnant patients who were treated with remdesivir (March 21 to June 16, 2020) have been published. Recovery rates were high among those who received remdesivir (67 while pregnant and 19 on postpartum days 0-3). No new safety signals were observed. At baseline, 40% of pregnant patients (median gestational age, 28 weeks) required invasive ventilation compared with 95% of postpartum patients (median gestational age at delivery, 30 weeks). Among pregnant individuals, 93% of those on mechanical ventilation were extubated, 93% recovered, and 90% were discharged. Among postpartum patients, 89% were extubated, 89% recovered, and 84% were discharged. There was 1 maternal death attributed to underlying disease, and no neonatal deaths. ^[31]

Data continue to emerge. A case series of 5 patients describes successful treatment and monitoring throughout treatment with remdesivir in pregnant individuals with COVID-19. ^[32]  

Outpatient remdesivir 

Remdesivir is approved by the FDA for outpatient use in nonhospitalized adults and pediatric patients (birth and older who weigh at least 1.5 kg) with mild-to-moderate COVID-19 who are at high risk for progression to severe disease, including hospitalization or death.  

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, remdesivir demonstrated an 87% lower risk for hospitalization or death compared with 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. ^[33]  

Drug interactions with remdesivir

Coadministration of remdesivir is not recommended with chloroquine or hydroxychloroquine. Based on in vitro data, chloroquine demonstrated an antagonistic effect on the intracellular metabolic activation and antiviral activity of remdesivir. ^[34]

Nirmatrelvir/ritonavir

Nirmatrelvir/ritonavir (Paxlovid) was granted full FDA approval May 26, 2023 for adults, while the EUA granted December 22, 2021 for treatment of mild-to-moderate COVID-19 remains in effect for pediatric patients aged 12 years and older who weigh at least 40 kg. It is indicated for those who 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 for 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). ^[35]

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. ^[36]   

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. ^[37]    

A retrospective study conducted by the Missouri Veterans Affairs observed outpatients treated with nirmatrelvir/ritonavir within 5 days of testing positive for COVID-19 (n = 9,217) reduce the risk for long COVID compared with untreated outpatients (n = 47,123). ^[38]   

An open-label, multicenter, randomized trial determined nirmatrelvir/ritonavir did not reduce the risk for all-cause mortality on day 28 in hospitalized adults. Criteria included hospitalized adults with severe comorbidities, confirmed SARS-CoV-2 infection by positive real-time PCR within the previous 48 hours, and duration from symptom onset to hospital admission less than 5 days. ^[39]  

Antivirals with EUAs

Symptom/viral rebound 

Concerns regarding antiviral agents, particularly nirmatrelvir/ritonavir (Paxlovid) causing rebound of symptoms were vocalized in the press and social media. The course of viral infections with fluctuating viral loads and symptoms is not unique to SARS-CoV 2. However, studies have shown no difference in risk for viral rebound among nirmatrelvir/ritonavir compared with control groups that included usual care, placebo, and/or another drug (eg, other antiviral agent, monoclonal antibodies). ^{[40, 41]}   

Symptom rebound and viral rebound has been described in patients with COVID-19 (with or without antiviral treatment). In untreated patients (n = 563) receiving placebo in the ACTIV-2/A5401 (Adaptive Platform Treatment Trial for Outpatients with COIVD-19) platform trial recorded 13 symptoms daily between days 1 and 28. Symptom rebound was identified in 26% of participants at a median of 11 days after initial symptom onset. Viral rebound was detected in 31% and high-level viral rebound in 13% of participants. ^[42]   

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 and who are at high risk for progression to severe COVID-19, including hospitalization or death. 

Molnupiravir (MK-4482 [previously EIDD-2801]; Merck and Ridgeback Biotherapeutics) 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 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. ^[43]  

A real world analysis among United States veterans between January 5th and September 30th 2022 utilized medical records to measure hospital admission or death at 30 days in patients who received molnupiravir (N = 85,998) or no treatment (N = 78,180). Molnupiravir was associated with a reduction in hospital admissions or death at 30 days (relative risk 0.72) compared with no treatment; the event rates for hospital admission or death at 30 days were 2.7% for molnupiravir and 3.8% for no treatment; the absolute risk reduction was 1.1%. ^[44]   

Earlier population-based real-world data from the largest healthcare provider in Israel were analyzed to evaluate molnupiravir efficacy. The study identified 2,661 adults with a first-ever positive test for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) performed in the community during January–February 2022, who were at high risk for severe COVID-19. Study outcomes were defined as the composite of severe COVID-19 or COVID-19-specific mortality, specifically – O2 sat < 94% on room air, PaO2 < 300 mmHg, or RR >30 b/m. Molnupiravir was associated with a nonsignificant reduced risk for the composite outcome. However, subgroup analyses showed that molnupiravir was associated with a significant decrease in risk for the composite outcome in older patients, in females, and in patients with inadequate COVID-19 vaccination. The results were similar when each component of the composite outcome was examined separately. ^[45]

Molnupiravir was 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. Molnupiravir did not demonstrate a statistically significant reduction in the risk of COVID-19 following household exposure. ^[46]   

Other Investigational Antivirals 

Ensitrelvir

Ensitrelvir fumaric acid (Shionogi Pharmaceuticals) is an oral 3CL protease inhibitor. SARS-CoV-2 has an enzyme called 3CL protease, which is essential for the replication of the virus. Ensitrelvir suppresses the replication of SARS-CoV-2 by selectively inhibiting 3CL protease. The phase 3 SCORPIO-SR study (N = 1821) evaluated efficacy and safety in patients with mild-to-moderate COVID-19 in Japan, South Korea, and Vietnam. Patients received ensitrelvir 125 mg orally (375 mg on day 1; n = 347), ensitrelvir 250 mg orall (750 mg on day 1; n = 340), or placebo (n = 343) once daily for 5 days. Treatment was initiated within 5 days of onset of symptoms. Results showed a statistically significant reduction in time to resolution of symptoms between the 125-mg ensitrelvir group and the placebo group (167.9 h vs 192.2 h; P = 0.0407). Additionally, a significant reduction in time to achieve negative infectious viral titer was observed with ensitrelvir compared with placebo (36.2 h vs 65.3 h; P < 0.001). ^[47]   

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. ^[48]  A recently completed multinational phase 2/3 clinical trial of opaganib in patients hospitalized with COVID-19 demonstrated that opaganib resulted in a 62% decrease in mortality in a large subpopulation of patients with moderately severe Covid-19. ^[49]  

Sabizabulin 

Sabizabulin (VERU-111; Veru, Inc) is an oral microtubule depolymerization agent that has broad antiviral activity and has strong anti-inflammatory effects. ^[50]  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 24% absolute reduction and a 55.2% relative reduction in deaths compared with placebo (p = 0.0042). Sabizabulin treatment resulted in a 43% relative reduction in ICU days (p = 0.0013), a 49% relative reduction in days on mechanical ventilation (p = 0.0013), and a 26% relative reduction in days in the hospital (p = 0.0277) compared with placebo. ^[51]   

Bemnifosbuvir

Bemnifosbuvir (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. 

The FDA granted fast track designation to bemnifosbuvir, which is being evaluated in the global Phase 3 SUNRISE-3 trial for the treatment of COVID-19 in outpatients at high risk for disease progression regardless of vaccination status. This includes patients over the age of 80, patients 65 years or older with at least 1 major risk factor, and anyone over the age of 18 who is immunocompromised. ^[52]  

Clinical trials of existing drugs with 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. A systematic review of 5 blinded, placebo-controlled randomized clinical trials showed no evidence of clinical benefits to treat patients with mild or moderate COVID-19. A reduction in WBC, LDH, and D-dimer levels among nitazoxanide-treated patients was observed, but the effect size was considered small to moderate. ^[53]   

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. ^[54]  A phase 2/3 trial is testing safety and the potential to improve outcomes and reduce hospital stay by reducing viral load. ^[55]  

 

Table 1. Other Investigational Antivirals for COVID-19 (Open Table in a new window)

Early in the pandemic, drugs (eg, interleukin inhibitors, Janus kinase inhibitors, interferons) were identified that may modulate the immunologic pathways associated with the hyperinflammation observed with COVID-19. ^{[63, 64]}  Since then, several have been approved by the FDA (ie, baricitinib) or have been granted emergency use authorization (ie, tocilizumab, anakinra). 

A study comparing baricitinib and tocilizumab found no difference in mortality between the 2 treatments. Occurrence of adverse effects was higher in the tocilizumab treated patients compared with baricitinib, including secondary infections (32% vs 22%; p < 0.01); thrombotic events (24% vs 16%; p < 0.01); and acute liver injury (8% vs 3%; p < 0.01). ^{[65, 66]}  

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 then is 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, also is identified as a NAK inhibitor with a particularly high affinity for AAK1. ^{[67, 68, 69]}  

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. 

An 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) compared with remdesivir alone. The multinational trial included 1033 patients (515 received baricitinib plus remdesivir and 518 received control [remdesivir plus placebo]). Results demonstrated 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.

Additionally, 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; 95% CI, 1.10 - 2.08). The 28-day mortality was 5.1% in the combination group and 7.8% in the control group (hazard ratio for death, 0.65; 95% CI, 0.39 - 1.09). 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). ^[70]  

The COV-BARRIER trial demonstrated baricitinib to be the first immunomodulatory treatment to reduce COVID-19 mortality in a placebo-controlled trial. ^[71]  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. ^[72]  

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). ^[73]

Tofacitinib

Tofacitinib (Xeljanz), another JAK inhibitor, was evaluated in 289 hospitalized patients with COVID-19 pneumonia who 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. ^[74]  

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. 

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. ^[75]  

Tocilizumab 

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 ECMO. The FDA granted full approval for this indication for adults in December 2022. The EUA remains in place for children. 

The Infectious Diseases 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. ^[7]  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. ^[76]  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 of progressing to mechanical ventilation or death by day 28 compared with those not treated with tocilizumab (n = 128) (12% vs 19.3% respectively; P = 0.04). 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. ^[77]

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. ^[78]  

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. ^[79]  

The RECOVERY trial assessed use of 4,116 hospitalized adults with COVID-19 infection who received tocilizumab (n = 2,022) compared with standard of care (n = 2,094) 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. The primary outcome of all-cause mortality within 28 days of randomization occurred in 35% of the usual care group compared with 31% of those who received tocilizumab (P = 0.0028). 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 < 0.0005). ^[80]  

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). ^[81]

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 received glucocorticoids in the tocilizumab group (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. ^[82]  

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

Interleukin-1 inhibitors

Anakinra

Anakinra was issued an EUA on November 8, 2022 for treatment of COVID-19 pneumonia in hospitalized adults on supplemental oxygen (low- or high-flow) who are at risk of progressing to severe respiratory failure and likely to have an elevated plasma soluble urokinase plasminogen activator receptor (suPAR). 

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 suPAR serum levels, which is an early indicator of progressing respiratory failure. Results showed the anakinra-treated group was associated with lower odds of more severe disease at day 28 compared with placebo There were 13 deaths (3.2%) in the anakinra arm and 13 deaths (6.9%) in the placebo arm. Also by day 28, there were 86 patients (21.2%) in the anakinra arm and 62 patients (32.8%) in the placebo arm who developed severe respiratory failure. Additionally, by day 60, there were 21 deaths (5.3%) in the anakinra arm and 18 deaths (9.7%) in the placebo arm. ^[83]  

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 July 2020, the NIH guidelines note insufficient data to recommend for or against use of IL-1 inhibitors. ^[84]  

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 United Kingdom to assess immune reconstitution in lymphopenic patients with COVID-19. ^{[85, 86, 87]} 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 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%). ^[88]

Corticosteroids generally are not recommended for treatment of viral pneumonia. ^[89] 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 needed 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. ^[90]

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. ^[91] The results from the RECOVERY trial in June 2020 provided evidence for clinicians to consider when low-dose corticosteroids would be beneficial. ^[88]

Several trials examining use of corticosteroids for COVID-19 were halted following 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). ^[92]  An accompanying editorial addresses the unanswered questions regarding these studies. ^[93]  

WHO guidelines for use of dexamethasone (6 mg IV or oral) or hydrocortisone (50 mg IV every 8 hours) for 7 to 10 days in the most seriously ill patients coincide with publication of the meta-analysis. ^[94]  

Complement Inhibitors 

Poor COVID-19 disease outcomes have been associated with activation of the complement system, specifically the C5a-C5aR axis. ^{[95, 96]}  Studies have shown C5a attracts neutrophils and monocytes to the infection site, which may lead to tissue damage, endothelialitis, and microthrombosis. ^[97]  

Vilobelimab 

Vilobelimab (Gohibic; InflaRx) was granted an EUA by the FDA on April 4, 2023 for treatment of coronavirus disease 2019 (COVID-19) in hospitalized adults when initiated within 48 hr of receiving invasive mechanical ventilation (IMV) or extracorporeal membrane oxygenation (ECMO). It is a chimeric human/mouse immunoglobulin G4 (IgG4) antibody consisting of mouse anti-human complement factor 5a (C5a) monoclonal binding sites. 

Evidence from the multicenter, double-blind, randomized, placebo-controlled phase 3 PANAMO trial reported results from 369 patients who were randomly assigned to receive vilobelimab (n =177) or placebo (n = 191). Both groups received standard of care (eg, anticoagulants, dexamethasone, and/or other immunomodulators). The data estimated 28-day mortality rate was 31.7% in the vilobelimab group compared with 41.6% with placebo (p < 0.05), which correlated to a 23.9% risk reduction. ^[98]   

Interferons

Interferon lambda

Receptors for lambda-interferon generally are located in the lining of the lungs, airways, and intestine – the locations where SARS-CoV-2 often is introduced. An international study in Canada and Brazil showed a single subcutaneous injection of peglylated interferon lambda in outpatients significantly reduced the incidence of hospitalization or an emergency room visit (for < 6 hours) compared with placebo. Nonhospitalized patients were administered 180 mg SC of pegylated interferon lambda (n = 933) or placebo (n = 1018). The effects were consistent across dominant variants and independent of vaccination status. ^[99]  

Interferon beta-1a

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 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%). ^[100]

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) 4-fold 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. ^[101]   

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.

The nebulized form of aviptadil in the I-SPY COVID trial in critical patients was stopped in early 2022 as it suggested no clinical benefit with inhaled administration. ^[102]

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 randomized 59 (30 to fostamatinib and 29 to placebo) hospitalized patients with COVID-19 to receive fostamatinib or placebo in addition to standard of care. Three deaths occurred by day 29, all of whom were in the placebo group. 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). ^[103]   

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. 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. ^[104] 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. ^{[105, 106]}  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. ^[107]  

Adjunctive Nutritional Therapies

NIH guidelines state there is 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. ^[108]

Zinc

A retrospective analysis showed lack of a causal association between zinc and survival in hospitalized patients with COVID-19. ^[109]

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 [RR], 1.77; P = .02). Testing positive for COVID-19 also was associated with increasing age up to age 50 years (RR, 1.06; P = .02) and race other than White (RR, 2.54; P = .009). ^[110]  It is unknown if vitamin D deficiency is the specific issue, as it also is associated with various conditions that are risk factors for severe COVID-19 conditions (eg, advanced age, cardiovascular disease, diabetes mellitus). ^[111]  

A phase 2 (REsCue) trial has been completed for an extended-release formulation of calcifediol (25-hydroxyvitamin D3 [Rayaldee; OPKO Health]), a prohormone of the active form of vitamin D3. 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. ^[112]  

NIH immune modulators trial 

In October 2020, the NIH launched an adaptive phase 3 trial (ACTIV-Immune Modulators [IM]) to assess safety and efficacy of 3 immune modulator agents in hospitalized patients with Covid-19. The three drugs are infliximab (Remicade), abatacept (Orencia), and cenicriviroc, a late-stage investigational drug for hepatic fibrosis associated with nonalcoholic steatohepatitis.  

Infliximab

Monoclonal antibody that inhibits TNF, a proinflammatory cytokine that may cause excess inflammation during advanced stages of COVID-19. Initially approved in 1998 to treat various chronic autoimmune inflammatory diseases (eg, rheumatoid arthritis, psoriasis, inflammatory bowel diseases). 

Abatacept

Selective T-cell costimulatory immunomodulator. The drug consists of the extracellular domain of human cytotoxic T cell-associated antigen 4 fused to a modified immunoglobulin. It works by preventing full activation of T cells, resulting in inhibition of the downstream inflammatory cascade.

Cenicriviroc

An immunomodulator that blocks 2 chemokine receptors, CCR2 and CCR5, shown to be closely involved with the respiratory sequelae of COVID-19 and of related viral infections. It also is part of the I-SPY COVID-19 clinical trial. ^[12]  This study was discontinued due to futility at the recommendation of the Data and Safety Monitoring Board. 

Colony-stimulating factors

Granulocyte-macrophage colony stimulating factor (GM-CSF) is among cytokines that contribute to the pathogenesis of respiratory failure in patients with severe COVID-19 pneumonia and systemic hyperinflammation. 

Lenzilumab 

Lenzilumab (Humanigen) is a monoclonal antibody directed against GM-CSF. Results from the multicenter phase 3 LIVE-AIR trial (n = 520) found lenzilumab significantly improved survival without ventilation in hospitalized, hypoxic patients with COVID-19 pneumonia over and above treatment with remdesivir and/or corticosteroids. Corticosteroids and remdesivir were administered to 94% and 72% of patients respectively; 69% received both treatments. Survival without invasive mechanical ventilation to day 28 was achieved in 84% of the lenzilumab group and 78% of the placebo group. Likelihood of survival was greater with lenzilumab than placebo (p = 0.04). Those with C-reactive protein less than 150 mg/L and age younger than 85 years demonstrated an improvement in survival and had the greatest benefit. ^[113]   

Additionally, lenzilumab is part of the NIH ACTIV-5/BET trial that is ongoing as of April 2021. 

Sargramostim 

Sargramostim (Leukine, rhuGM-CSF; Partner Therapeutics, Inc) is an inhaled colony-stimulating factor. Results of the phase 2 trial (iLeukPulm) of inhaled sargramostim plus standard of care (SOC) in 122 hospitalized patients with confirmed SARS-CoV-2 infection with acute hypoxemia requiring supplemental oxygen were release in late June 2021. Patients on inhaled sargramostim plus SOC showed an average improvement in oxygenation from baseline, as measured by P(A-a)O2, of 100 mm Hg (31%) compared to 35 mm Hg (5%) on SOC alone (P = 0.033).  Improved oxygenation was observed in 84% of sargramostim-treated patients, compared with 64% in the control arm (P = 0.023). ^[114]  GM-CSF may reduce the risk for secondary infection, accelerate removal of debris caused by pathogens, and stimulate alveolar epithelial cell healing during lung injury. ^[115]  

Gimsilumab 

The phase 2 BREATHE clinical trial evaluated gimsilumab (Riovant Sciences) compared with placebo in hospitalized patients with COVID-19 who had elevated inflammatory markers and hypoxemia. Overall mortality rates at 24 weeks were similar across the treatment arms. Gimsilumab did not improve mortality or other key clinical outcomes in patients with COVID-19 pneumonia and evidence of systemic inflammation. ^[116]  

Mavrilimumab 

Mavrilimumab (Kiniksa Pharmaceuticals) is a fully humanized monoclonal antibody that targets granulocyte macrophage colony-stimulating factor (GM-CSF) receptor alpha. In the MASH-COVID trial (n = 40), there was no significant difference in the proportion of patients alive and off oxygen therapy at day 14, although benefit or harm of mavrilimumab therapy in this patient population remains possible given the wide confidence intervals. The researchers suggest a larger trials should be completed. ^[117]  

Otilimab

Otilimab (GlaxoSmithKline) is a humanized monoclonal anti-GM-CSF antibody under development for rheumatoid arthritis. A global, randomized trial (OSCAR; n = 806) compared a single 90-mg infusion of otilimab plus standard of care (SOC) with SOC alone in hospitalized adults with severe COVID-19 respiratory failure and systemic inflammation. At day 28, 71% of patients who received otilimab were alive and free of respiratory failure compared with 67% of SOC alone. Although this did not reach statistical significance in the entire population, benefit was observed for those aged 70 years and older (P = 0.009). This age group also had a reduction of 14.4% in all-cause mortality at day 60. These findings are being confirmed in a further cohort of patients aged 70 and older. ^[118]  

Namilumab 

A proof-of-concept trial (CATALYST) showed that the addition of namilumab, but not infliximab, to usual care reduced inflammation as measured by C-reactive protein concentration in hospitalized patients with COVID-19, compared with usual care alone. Confirmation in a larger phase 3 trial is warranted. ^[119]   

Neurokinin-1 (NK-1) receptor antagonists

Tradipitant 

Tradipitant (Vanda Pharmaceuticals) is an NK-1 receptor antagonist. The NK-1 receptor is genetically coded by TACR1 and it is the main receptor for substance P. The substance P NK-1 receptor system is involved in neuroinflammatory processes that lead to serious lung injury following numerous insults, including viral infections. ODYSSEY phase 3 trial in severe or critical COVID-19 infection reported an interim analysis on August 18, 2020.  Patients who received tradipitant recovered earlier than those receiving placebo. ^{[120, 121]}  

Aprepitant 

Aprepitant (Cinvanti; Heron Therapeutics) is a substance P/neurokinin-1 (NK1) receptor antagonist. Substance P and its receptor, NK1, are distributed throughout the body in the cells of many tissues and organs, including the lungs. Phase 2 clinical study (GUARDS-1) initiated mid-July 2020 in early-hospitalized patients with COVID-19. Administration to these patients is expected to decrease production and release of inflammatory cytokines mediated by the binding of substance P to NK1 receptors, which could prevent the progression of lung injury to ARDS. ^[122]

Mesenchymal stem cells

NIH guidelines recommend against use of mesenchymal stem cell for COVID-19 except in a clinical trial. 

ExoFlo

ExoFlo (Direct Biologics), a bone marrow mesenchymal stem cell derived extracellular vesicles, continues to be studied as of April 2023 based on positive survival benefit observed in the phase 2 EXIT-COVID19 trial. ^[123]  The EXTINGUISH ARDS phase 3 trial is evaluating efficacy for treatment of all-cause moderate-to-severe ARDS. ^[124]    

Remestemcel-L 

Remestemcel-L (Ryoncil; Mesoblast Ltd) is an allogeneic mesenchymal stem cell (MSC) product currently pending FDA approval for graft versus host disease (GVHD). As of December 2020, a phase 3 study in 222 ventilator-dependent COVID-19 patients with moderate to severe ARDS was halted early for showing no signs of reducing death in patients over the age of 65 years. Remestemcel-L showed a 48% reduction in death for patients younger than 65 years after 90 days. ^[125]

PLX-PAD 

PLX-PAD (Pluristem Therapeutics) contains allogeneic mesenchymal-like cells with immunomodulatory properties that induce the immune system’s natural regulatory T cells and M2 macrophages. Results from a phase 2 study in mechanically ventilated patients with severe COVID-19 did not meet the primary efficacy endpoint of statistically significant improvement of ventilator free days at 28 days. ^[126]  

Other mesenchymal stem cell candidates

Additional product candidates include BM-Allo.MSC (NantKwest, Inc), ^[127]  HB-adMSC (Hope Biosciences),128 and hCT-MSC ^[128] ).

Phosphodiesterase inhibitors

Ibudilast 

Ibudilast (MN-166; MediciNova) is a first-in-class, orally bioavailable, small molecule phosphodiesterases (PDE) 4 and 10 inhibitor and a macrophage migration inhibitory factor (MIF) inhibitor that suppresses proinflammatory cytokines and promotes neurotrophic factors. The drug has been approved in Japan and South Korea since 1989 to treat post-stroke complications and bronchial asthma. An IND for a phase 2 trial in the United States to prevent ARDS has been accepted by the FDA. ^[129]

Apremilast 

Apremilast (Otezla; Amgen Inc) is a small-molecule inhibitor of phosphodiesterase 4 (PDE4) specific for cyclic adenosine monophosphate (cAMP). PDE4 inhibition results in increased intracellular cAMP levels, which may indirectly modulate the production of inflammatory mediators. Apremilast was part of the I-SPY COVID-19 clinical trial, a phase II, open label, adaptive platform trial being conducted in critically ill COVID-19 patients who are receiving high flow oxygen or mechanical ventilation. Apremilast was dropped from the study for futility, as it did not alter the clinical course of critically ill COVID-19 ARDS patients when added to dexamethasone and/or remdesivir.    

Table 2. Investigational Drugs for ARDS/Cytokine Release Associated With COVID-19 (Open Table in a new window)

 

  Table 3. Investigational Immunotherapies for COVID-19 (Open Table in a new window)

COVID-19 convalescent plasma

The FDA granted emergency use authorization (EUA) on August 23, 2020 for use of COVID-19 convalescent plasma (CCP) in hospitalized patients. Convalescent plasma contains antibody-rich plasma products collected from eligible donors who have recovered from COVID-19. The EUA limits the authorization to use CCP products that contain high levels of anti-SARS-CoV-2 antibodies for treatment of outpatients or inpatients with COVID-19 who have immunosuppressive disease or who are receiving immunosuppressive treatment. ^[189]   

As of January 2023, high-titer CCP once again has become important to immunosuppressed patients since the EUAs for monoclonal antibodies have been revoked owing to SARS-CoV-2 variants that are no longer susceptible. A systematic review and meta-analysis concluded that transfusion of CCP is associated with decreasing mortality among patients who are immunocompromised and have COVID-19. ^[190]   

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. ^[191]     

Monoclonal Antibodies

Preexposure prophylaxis (PrEP)

Pemivibart (Pemgarda; VYD222; Invivyd) was granted emergency use authorization (EUA) by the FDA in March 2024. Pemivibart has an extended half-life making it suitable for patients who have moderate-to-severe immune compromise due to certain medical conditions (eg, hematologic malignancies, solid organ or stem cell transplant) or receipt of immunosuppressive medications and are unlikely to mount an adequate immune response wot a COVID-19 vaccine. The EUA was granted based on interim data from the Phase 3 CANOPY study. (REF)

Earlier EUAs for monoclonal antibodies were paused in 2022 and early 2023 owing to a high frequency of circulating SARS-CoV-2 variants that were non-susceptible.

Monoclonal Antibodies Whose Distribution is Paused

Distribution of the following monoclonal antibodies has been paused in the United States owing to loss of efficacy to the viral variants. 

Table 4. SARS-CoV-2 Monoclonal Antibodies – inactive EUAs (Open Table in a new window)

 

  Table 5. Investigational Antibody-Directed Therapy Examples for COVID-19 (Open Table in a new window)

Two vaccines have gained full approval from the FDA – mRNA vaccine (Comirnaty; Pfizer) and mRNA vaccine (Spikevax; Moderna). Other SARS-CoV-2 vaccines available in the United States through emergency use authorization include an adjuvanted protein subunit vaccine – NVX-CoV2373 (Novavax) and a viral vector vaccine – Ad26.COV2.S (Johnson & Johnson). Two bivalent vaccines for use as boosters were granted EUAs in August 2022 to include enhanced coverage for Omicron BA.4/BA.5 subvariants. The FDA also has authorized the monovalent adjuvanted vaccines from Novavax as a first booster in adults. For full discussion regarding vaccines, see COVID-19 Vaccines. 

The genetic sequence of SARS-CoV-2 was published on January 11, 2020. A rapid emergence of research and collaboration among scientists and biopharmaceutical manufacturers followed. 

In addition to the complexity of finding the most effective vaccine candidates, the production process also is important for manufacturing the vaccine to the scale needed globally. Other variables 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. ^{[206, 207]}   

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. ^[208]  While sepsis is recognized to activate the coagulation system, the precise mechanism by which COVID-19 inflammation affects coagulopathy is not fully understood. ^[209]   

Several retrospective cohort studies have described the 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. ^[210]  

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. ^[211]   

NIH trial

Current guidelines include thrombosis prophylaxis (typically with low-molecular-weight heparin [LMWH]) for hospitalized patients. As of September 2020, 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 randomly assigned 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. ^[212]   

Inpatient trial 

An 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 may cause harm compared with those given usual-care thromboprophylaxis (ie, thromboprophylactic dose anticoagulation according to local practice). Among moderately ill patients, the likelihood of full-dose heparin to reduce the need for organ support compared with 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. ^{[213, 214]}  

Convalescent trial

The convalescent trial investigates safety and efficacy of apixaban administered to patients who have been discharged from the hospital or who 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. Tissue factor 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 is change in D-dimer level from baseline to day 8. The phase 3 trial design is contingent upon phase 2b results. ^[215]  

SARS-CoV-2 is known to utilize angiotensin-converting enzyme 2 (ACE2) receptors for entry into target cells. ^[216] 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 two 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). ^[217]  

The BRACE Corona trial design further explains the two hypotheses. ^[217]  

• 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 often are treated with ACEIs and ARBs. The reason for this association remains unclear. ^{[218, 219]}

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 ^[218] ; 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. ^{[219, 220]} It therefore is uncertain whether an increased expression of ACE2 receptors would worsen or mitigate the effects of SARS-CoV-2 in human lungs.

Vaduganathan et al 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. ^[221]

There also are conflicting data regarding whether ACEIs and ARBs increase ACE2 levels. Some studies in animals have suggested that ACEIs and ARBs increase expression of ACE2, ^{[222, 223, 224]} whereas other studies have not shown this effect. ^{[225, 226]}

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 largely have recommended against initiating or discontinuing these medications based solely on active SARS-CoV-2 infection. ^{[227, 228]}

A systematic review and meta-analysis found use of ACEIs or ARBs was not associated with a higher risk for 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. ^[229]

 

High plasma glucose levels and diabetes mellitus (DM) are known risk factors for pneumonia. ^{[230, 231]} Potential mechanisms that may increase the susceptibility for COVID-19 in patients with DM include the following ^[232] :

• 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 ^[216] for entry into target cells. Insulin administration attenuates ACE2 expression, while hypoglycemic agents (eg, glucagonlike peptide 1 [GLP-1] agonists, thiazolidinediones) up-regulate ACE2. ^[232] 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. ^[233]

The relationship between diabetes, coronavirus infections, ACE2, and DPP-4 has been reviewed by Drucker. Important clinical conclusions of the review include the following ^[231] :

• 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.

Hydroxychloroquine or chloroquine

An EUA was issued for treatment of COVID-19 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. ^[234]

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. 

Hydroxychloroquine and chloroquine are widely used antimalarial drugs that elicit immunomodulatory effects and therefore are also used to treat autoimmune conditions (eg, systemic lupus erythematosus, rheumatoid arthritis). As inhibitors of heme polymerase, they also are believed to have additional antiviral activity via alkalinization of the phagolysosome, which inhibits the pH-dependent steps of viral replication. Wang et al reported that chloroquine effectively inhibits SARS-CoV-2 in vitro. ^[235] The pharmacologic activity of chloroquine and hydroxychloroquine was tested using SARS-CoV-2–infected Vero cells. Physiologically based pharmacokinetic models (PBPK) were conducted for each drug.

Hydroxychloroquine was found to be more potent than chloroquine in vitro. Based on PBPK models, the authors recommend a loading dose of hydroxychloroquine 400 mg PO BID, followed by 200 mg BID for 4 days. ^[91]

Published reports stemming from the worldwide outbreak of COVID-19 have evaluated the potential usefulness of these drugs in controlling cytokine release syndrome in critically ill patients. Owing to widely varying dosage regimens, disease severity, measured outcomes, and lack of control groups, efficacy data have been largely inconclusive.

The UK RECOVERY Trial randomly assigned 1561 patients to hydroxychloroquine and 3155 patients to usual care alone. Results found no significant difference in the primary endpoint of 28-day mortality (27% hydroxychloroquine vs 25% usual care; hazard ratio 1.09; P = 0.15). Secondary outcomes showed patients in the hydroxychloroquine group had a longer duration of hospitalization than those in the usual-care group (median, 16 days vs 13 days) and a lower probability of discharge alive within 28 days (59.6% vs 62.9%; rate ratio, 0.90). ^[236]

A multicenter, randomized, open-label trial in Brazil found no improvement in 504 hospitalized patients with mild-to-moderate COVID-19. Use of hydroxychloroquine, alone or with azithromycin, did not improve clinical status at 15 days compared with standard care. Prolonged QTc interval and elevated liver-enzyme levels were more common in patients receiving hydroxychloroquine, alone or with azithromycin, than in those who were not receiving either agent. ^[237]

An observational study of 2512 hospitalized patients in New Jersey with confirmed COVID-19 was conducted between March 1, 2020, and April 22, 2020, with follow-up through May 5, 2020. Outcomes included 547 deaths (22%) and 1539 (61%) discharges; 426 (17%) remained hospitalized. Patients who received at least one dose of hydroxychloroquine totaled 1914 (76%), and those who received hydroxychloroquine plus azithromycin totaled 1473 (59%). No significant differences were observed in associated mortality among patients receiving any hydroxychloroquine during the hospitalization (HR, 0.99), hydroxychloroquine alone (HR, 1.02), or hydroxychloroquine with azithromycin (HR, 0.98). The 30-day unadjusted mortality rate in patients receiving hydroxychloroquine alone, azithromycin alone, the combination, or neither drug was 25%, 20%, 18%, and 20%, respectively. ^[238]

Because of findings from the aforementioned studies, the WHO halted the hydroxychloroquine arm of the Solidarity Trial and then removed its use entirely as of July 4, 2020. ^[13] Interim results released mid-October 2020 found hydroxychloroquine and chloroquine 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 ratio for hydroxychloroquine was 1.19 (104/947 vs 84/906; P = 0.23). ^[14]  The FDA issued a safety alert for hydroxychloroquine or chloroquine use in COVID-19 on April 24, 2020 and revoked the EUA on June 15, 2020. ^{[239, 240]}  

A multicenter, blinded, placebo-controlled randomized trial conducted at 34 hospitals in the United States showed hydroxychloroquine did not significantly improve clinical status at day 14 in adults who were hospitalized with COVID-19 respiratory illness. Patients were randomly assigned to hydroxychloroquine (400 mg twice daily for 2 doses, then 200 mg twice daily for 8 doses) (n = 242) or placebo (n = 237). ^[241]

An observational study of consecutively hospitalized patients (n = 1446) at a large medical center in the New York City area showed hydroxychloroquine was not associated with either a greatly lowered or an increased risk for the composite endpoint of intubation or death. ^[242]

A nationwide, observational cohort study in the Netherlands showed early treatment with hydroxychloroquine (but not chloroquine) on the first day of hospital admission was associated with a 53% reduced risk for transfer to the ICU for mechanical ventilation. Hospitals were given the opportunity to decide independently on the use of three different treatment strategies: hydroxychloroquine (n = 189), chloroquine (n = 377), or no treatment (n =498). The authors concluded that additional prospective data on early hydroxychloroquine use is still needed. ^[243]  

A retrospective observational study of 2,541 consecutive patients hospitalized with COVID at Henry Ford Health System from March 10, 2020, to May 2, 2020, showed a decreased mortality rate in patients treated with hydroxychloroquine alone or in combination with azithromycin. Overall in-hospital mortality was 18.1% (hydroxychloroquine plus azithromycin, 157/783 [20.1%], hydroxychloroquine alone, 162/1202 [13.5%], azithromycin alone, 33/147 [22.4%], and neither drug, 108/409 [26.4%]). Therapy with corticosteroids (methylprednisolone and/or prednisone) was administered in 68% of all patients. Corticosteroids were administered to 78.9% of patients who received hydroxychloroquine alone. In addition to adjunctive use of corticosteroids, an accompanying editorial discusses time bias, missing prognostic indicators, and other confounding factors of this observational study. ^{[244, 245]}

A retrospective analysis of data from patients hospitalized with confirmed COVID-19 infection in all US Veterans Health Administration medical centers between March 9, 2020, and April 11, 2020, has been published. Patients who had received hydroxychloroquine (HC) alone or with azithromycin (HC + AZ) as treatment in addition to standard supportive care were identified. A total of 368 patients were evaluated (HC, n=97; HC + AZ, n=113; no HC, n=158). Death rates in the HC, HC + AZ, and no-HC groups were 27.8%, 22.1%, and 11.4%, respectively. Rates of ventilation in the HC, HC + AZ, and no-HC groups were 13.3%, 6.9%, and 14.1%, respectively. The authors concluded that they found no evidence that hydroxychloroquine, with or without azithromycin, reduced the risk for mechanical ventilation and that the overall mortality rate was increased with hydroxychloroquine treatment. Furthermore, they stressed the importance of waiting for results of ongoing, prospective, randomized controlled trials before wide adoption of these drugs. ^[246]

A retrospective study assessed effects of hydroxychloroquine according to its plasma concentration in patients hospitalized in the ICU. The researchers compared 17 patients with hydroxychloroquine plasma concentrations within the therapeutic target and 12 patients with plasma concentrations below the target. At 15 days of follow-up, no association was found between hydroxychloroquine plasma concentration and viral load evolution (P = 0.77). Additionally, there was no significant difference between the two groups for duration of mechanical ventilation, length of ICU stays, in-hospital mortality, and 15-day mortality. ^[247]

According to a consensus statement from a multicenter collaboration group in China, chloroquine phosphate 500 mg (300 mg base) twice daily in tablet form for 10 days may be considered in patients with COVID-19 pneumonia. ^[248]  Although no peer-reviewed treatment outcomes are available, Gao and colleagues report that 100 patients have demonstrated significant improvement with this regimen without documented toxicity. ^[249] It should be noted this is 14 times the typical dose of chloroquine used per week for malaria prophylaxis and 4 times that used for treatment. Cardiac toxicity should temper enthusiasm for this as a widespread cure for COVID-19. It also should be noted that chloroquine was previously found to be active in vitro against multiple other viruses but has not proven fruitful in clinical trials, even resulting in worse clinical outcomes in human studies of Chikungunya virus infection (a virus unrelated to SARS-CoV-2).

A randomized controlled trial in Wuhan, China, enrolled 62 hospitalized patients (average age, 44.7 years) with confirmed COVID-19. Additional inclusion criteria included age 18 years or older, chest CT scans showing pneumonia, and SaO₂/SPOs ratio of more than 93% (or PaOs/FIOs ratio >300 mm Hg). Patients with severe or critical illness were excluded. All patients enrolled in the study received standard treatment (oxygen therapy, antiviral agents, antibacterial agents, and immunoglobulin, with or without corticosteroids). Thirty-one patients were randomly assigned to receive hydroxychloroquine sulfate (200 mg PO BID for 5 days) in addition to standardized treatment. Changes in time to clinical recovery (TTCR) was evaluated and defined as return of normal body temperature and cough relief, maintained for more than 72 hours. Compared with the control group, TTCR for body temperature and cough were significantly shortened in the hydroxychloroquine group. Four of the 62 patients progressed to severe illness, all of whom were in the control group. ^[250]

An open-label multicenter study using high-dose hydroxychloroquine or standard of care did not show a difference at 28 days for seronegative conversion or the rate of symptom alleviation between the two treatment arms. The trial was conducted in 150 patients in China with mild-to-moderate disease. ^[251]

Hydroxychloroquine plus azithromycin

Opposing conclusions by French researchers regarding viral clearance and clinical benefit with the regimen of hydroxychloroquine plus azithromycin have been published. ^{[252, 253, 254]}

A small prospective study found no evidence of a strong antiviral activity or clinical benefit from use of hydroxychloroquine plus azithromycin. Molina et al assessed virologic and clinical outcomes of 11 consecutive patients hospitalized who received hydroxychloroquine (600 mg per day x10 days) and azithromycin (500 mg day 1, then 250 mg days 2-5). Patient demographics were as follows: 7 men and 4 women; mean age 58.7 years (range: 20-77); 8 had significant comorbidities associated with poor outcomes (ie, obesity 2; solid cancer 3; hematological cancer 2; HIV-infection 1). Ten of the eleven patients had fever and received oxygen via nasal cannula. Within 5 days, 1 patient died and 2 were transferred to the ICU. Hydroxychloroquine and azithromycin were discontinued in 1 patient owing to prolonged QT interval. Nasopharyngeal swabs remained positive for SARS-CoV-2 RNA in 8/10 patients (80%) at days 5-6 after treatment initiation. ^[254]

In direct contrast to aforementioned results, another study in France evaluated patients treated with hydroxychloroquine (N=26) against a control group (n=16) who received standard of care. After dropping 6 patients who received treatment from the analysis for having incomplete data, the 20 remaining patients receiving hydroxychloroquine (200 mg PO q8h) had improved nasopharyngeal clearance of the virus on day 6 (70% [14/20] vs 12.5% [2/16]). ^[252] This is an unusual approach to reporting results because the clinical correlation with nasopharyngeal clearance on day 6 is unknown and several patients changed status within a few days of that endpoint (converting from negative back to positive). The choice of that particular endpoint was also not explained by the authors, yet 4 of the 6 excluded patients had adverse outcomes (admission to ICU or death) at that time but were not counted in the analysis. Furthermore, patients who refused to consent to the study group were included in the control arm, indicating unorthodox study enrollment.

This small open-label study of hydroxychloroquine in France included azithromycin in 6 patients for potential bacterial superinfection (500 mg once, then 250 mg PO daily for 4 days). These patients were reported to have 100% clearance of SARS-CoV-2. While intriguing, these results warrant further analysis. The patients receiving combination therapy had initially lower viral loads, and, when compared with patients receiving hydroxychloroquine alone with similar viral burden, the results are fairly similar (6/6 vs 7/9). ^[252]

The French researchers continued their practice of using hydroxychloroquine plus azithromycin and accumulated data in 80 patients with at least 6 days of follow-up. They note that the 6 patients on combination therapy enrolled in their first analysis were also included in the present case series, with a longer follow-up. However, it was not clear from the description in their posted methods when patients were assessed. A favorable outcome was defined as not requiring aggressive oxygen therapy or transfer to the ICU after 3 days of treatment. Sixty-five of the 80 patients (81.3%) met this outcome. One patient aged 86 years died, and a 74-year-old patient remained in the ICU. Two others were transferred to the ICU and then back to the infection ward.

Results showed a decrease in nasopharyngeal viral load tested via qPCR, with 83% negative at day 7 and 93% at day 8. Virus culture results from patient respiratory samples were negative in 97.5% of patients at day 5. ^[253] This is described as a promising method of reducing spread of SARS-CoV-2, but, unfortunately, the study lacked a control group and did not compare treatment with hydroxychloroquine plus azithromycin to a similar group of patients receiving no drug therapy or hydroxychloroquine alone. Overall, the acuity of these patients was low, and 92% had a low score on the national Early Warning System used to assess risk for clinical deterioration. Only 15% were febrile, a common criterion for testing in the United States, and four individuals were considered asymptomatic carriers. In addition, the results did not delineate between asymptomatic carriers and those with high viral load or low viral load.

Nonhospitalized patients with early COVID-19

Hydroxychloroquine did not improve outcomes when administered to outpatient adults (n = 423) with early COVID-19. Change in symptom severity over 14 days did not differ between the hydroxychloroquine and placebo groups (P = 0.117). At 14 days, 24% (49 of 201) of participants receiving hydroxychloroquine had ongoing symptoms compared with 30% (59 of 194) receiving placebo (P = 0.21). Medication adverse effects occurred in 43% (92 of 212) of participants receiving hydroxychloroquine compared with 22% (46 of 211) receiving placebo (P < 0.001). Among patients receiving placebo, 10 were hospitalized (two cases unrelated to COVID-19), one of whom died. Among patients receiving hydroxychloroquine, four were hospitalized and one nonhospitalized patient died (P = 0.29). ^[255]

Clinical trials evaluating prevention

Various clinical trials in the United States were initiated to determine if hydroxychloroquine reduces the rate of infection when used by individuals at high risk for exposure, such as high-risk healthcare workers, first responders, and individuals who share a home with a COVID-19–positive individual. ^{[256, 257, 258, 259, 260, 261]}

Results from the PATCH trial (n=125) did not show any benefit of hydroxychloroquine to reduce infection among healthcare workers compared with placebo. ^[258]

Another study enrolled 1483 healthcare workers, of which 79% of performed aerosol-generating procedures showed no difference in preventing infection with once or twice weekly hydroxychloroquine compared with placebo. The incidence of SARS-CoV-2 laboratory-confirmed or symptomatic compatible illness was 0.27 events per person-year with once-weekly and 0.28 events per person-year with twice-weekly hydroxychloroquine compared with 0.38 events per person-year with placebo (P = 0.18 and 0.22 respectively). ^[262]

Results from a double-blind randomized trial (n = 821) from the University of Minnesota found no benefit of hydroxychloroquine (n = 414) in preventing illness due to COVID-19 compared with placebo (n = 407) when used as postexposure prophylaxis in asymptomatic participants within 4 days following high-risk or moderate-risk exposure. Overall, 87.6% of participants had high-risk exposures without eye shields and surgical masks or respirators. New COVID-19 (either PCR-confirmed or symptomatically compatible) developed in 107 participants (13%) during the 14-day follow-up. Incidence of new illness compatible with COVID-19 did not differ significantly between those receiving hydroxychloroquine (49 of 414 [11.8%]) and those receiving placebo (58 of 407 [14.3%]); P = 0.35). ^[263]

QT prolongation with hydroxychloroquine and azithromycin

Chloroquine, hydroxychloroquine, and azithromycin each carry the warning of QT prolongation and can be associated with an increased risk for cardiac death when used in a broader population. ^[264] Because of this risk, the American College of Cardiology, American Heart Association, and the Heart Rhythm Society have published a thorough discussion of the arrhythmogenicity of hydroxychloroquine and azithromycin that includes a suggested protocol for clinical research QT assessment and monitoring when the two drugs are coadministered. ^[265]

A Brazilian study comparing 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) observed QT prolongation in 25% of patients in the high-dose group. All patients received other drugs (ie, azithromycin, oseltamivir) that may contribute to prolonged QT. ^[266]

An increased 30-day risk for cardiovascular mortality, chest pain/angina, and heart failure was observed with the addition of azithromycin to hydroxychloroquine from an analysis of pooled data from Japan, Europe, and the United States. The analysis compared use of hydroxychloroquine, sulfamethoxazole, or the combinations of hydroxychloroquine plus amoxicillin or hydroxychloroquine plus azithromycin. ^[267]

For more information, see QT Prolongation with Potential COVID-19 Pharmacotherapies. 

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 it 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. ^[268]

The Infectious Diseases Society of America (IDSA) guidelines recommend against 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. ^[7]

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 for progression to mechanical ventilation or length of hospital stay. ^[269]

The WHO discontinued use of lopinavir/ritonavir in the SOLIDARITY trial in hospitalized patients on July 4, 2020. ^[13]  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 (RR, 1.00; 148/1399 vs 146/1372; P = 0.97) and lopinavir plus interferon (RR=1.16; 243/2050 vs 216/2050; P = 0.11). ^[14]  

In a randomized, controlled, open-label trial of hospitalized adults (n=199) with confirmed SARS-CoV-2 infection, recruited patients had an oxygen saturation of 94% or less on ambient air or PaO₂ of less than 300 mm Hg and were receiving a range of ventilatory support modes (eg, no support, mechanical ventilation, ECMO). These patients were randomized to receive lopinavir/ritonavir 400 mg/100 mg PO BID for 14 days added to standard care (n=99) or standard care alone (n=100). Results showed that time to clinical improvement did not differ between the two groups (median, 16 days). The mortality rate at 28 days was numerically lower for lopinavir/ritonavir compared with standard care (19.2% vs 25%) but did not reach statistical significance. ^[270] An editorial accompanies this study that is informative regarding the extraordinary circumstances of conducting such a study in the midst of the outbreak. ^[271]

Another study (n = 86) that compared lopinavir/ritonavir or umifenovir monotherapy with standard care in patients with mild-to-moderate COVID-19 showed no statistical difference between each treatment group. ^[272]

A multicenter study in Hong Kong compared 14 days of triple therapy (n = 86) (lopinavir/ritonavir [400 mg/100 mg q12h], ribavirin [400 mg q12h], interferon beta1b [8 million IU x 3 doses q48h]) with lopinavir/ritonavir alone (n = 41). Triple therapy significantly shortened the duration of viral shedding and hospital stay in patients with mild-to-moderate COVID-19. ^[273]

Average wholesale price (AWP) for a course of lopinavir/ritonavir at this dose is $575. 

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 SARS-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 likely are not attainable in humans. ^[274]

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. ^[275]

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). ^[276]  

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. Ivermectin was initiated 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). ^[277]   

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. ^[278]    

Results from the ACTIV-6 NIH trial concluded 400 mcg/kg daily for 3 days resulted in less than 1 day of shortening of symptoms and did not lower incidence of hospitalization or death among outpatients with COVID-19 during the delta and omicron variant time periods. ^[279]  

The ACTIV-6 trial investigators also evaluated efficacy of ivermectin at a maximum targeted dose of 600 mcg/kg daily for 6 days among outpatients with early mild-to-moderate COVID-19. The median time to sustained recovery did not differ between the treated (n = 602) and placebo (n = 604) groups (ie, 11 days (range: 11-12 days. The hazard ratio (posterior probability of benefit) for improvement in time to recovery was 1.02 (95% credible interval, 0.92-1.13; p = 0.68). ^[280]   

Finally, the phase 3, double-blind COVID-OUT trial concluded ivermectin did not prevent occurrence of hypoxemia, emergency department visit, hospitalization, or death associated with COVID-19. ^[281]   

Fluvoxamine

In a murine sepsis model, fluvoxamine was found to bind to the sigma-1 receptor on immune cells, resulting in reduced production of inflammatory cytokines. Results from a small double-blind trial were encouraging. ^[282]    

The TOGETHER trial examined a primary outcome of clinical deterioration, defined as shortness of breath or hospitalization for shortness of breath or pneumonia, and oxygen saturation less than 92% on room air or need for supplemental oxygen to achieve oxygen saturation of 92% or greater. Within 15 days, none of the participants who received fluvoxamine and 8.3% of those who received placebo reached the primary endpoint (p = 0.009). Despite these promising results, limitations (ie, low statistical power and missing data for the primary outcome) precluded definitive conclusions regarding the efficacy of fluvoxamine for the treatment of COVID-19. ^[283]    

The phase 3, double-blind COVID-OUT trial concluded fluvoxamine did not prevent occurrence of hypoxemia, emergency department visit, hospitalization, or death associated with COVID-19. ^[281]   

The ACTIV-6 study group compared the efficacy of low-dose (50 mg BID) fluvoxamine (n = 674) for 10 days versus placebo (n = 614) in patients at least 30 years old with SARS-CoV-2 infection who were experiencing 2 or more symptoms of acute COVID-19 for less than 7 days. Median time to sustained recovery was 12 and 13 days in the fluvoxamine and placebo groups, respectively. Overall, 3.9 and 3.8% of participants in the fluvoxamine and placebo groups, respectively, had the composite outcome of hospitalization, urgent care visit, or emergency department visit through day 28. One and 2 participants in the fluvoxamine and placebo groups, respectively, were hospitalized. No deaths were reported in either group. Findings did not support fluvoxamine use at this dose for mild-to-moderate COVID-19. ^[284]   

Table 5. Other therapies determined ineffective (Open Table in a new window)

 

Chloroquine, hydroxychloroquine, and azithromycin each carry the warning of QT prolongation and can be associated with an increased risk for cardiac death when used in a broader population. ^[264] 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 on QT assessment and monitoring when the two drugs are coadministered. ^{[265, 293]}

Giudicessi et al 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. ^[294]

A retrospective study was performed by reviewing 84 consecutive adult patients who were hospitalized at NYU Langone Medical Center with COVID-19 and treated with hydroxychloroquine plus azithromycin. 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. ^[295]

A cohort study was performed from March 1 through April 7, 2020, at an academic tertiary care center in Boston 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. ^[296]

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. The high incidence of QT prolongation 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. ^[266]

Although not specific to patients with COVID-19, an increased 30-day risk for cardiovascular mortality, chest pain/angina, and heart failure was observed with the addition of azithromycin to hydroxychloroquine in a large study of administrative claims. 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. ^[267]

 

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. ^[297]

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. ^{[298, 299]}

 

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. Reports of increased patient mortality associated with some devices have emerged since the early part of pandemic as trials with these devices commenced.  

A single center, open-label trial investigate cytokine adsorption in adult patients with severe COVID-19 pneumonia requiring ECMO. Survival after 30 days was three (18%) of 17 with cytokine adsorption and 13 (76%) of 17 without cytokine adsorption (p=0·0016). Early use did not reduce serum IL-6 and had a negative effect on survival. ^[300]

Matson, et al examined 4 clinical studies of extracorporeal blood purification (EBP) treatments used in patients with sepsis and related conditions to mitigate toxic systemic inflammation, prevent or reverse vital organ injury, and improve outcome. Since late 2020, the 4 studies reported significantly increased patient mortality associated with the adsorbent treatments. ^[301]

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. ^[302]