February 25, 2021
The SARS-CoV-2 viral load in respiratory excretions rises rapidly during the several days before and after onset of symptoms. Because viral replication is particularly active at this early stage of SARS-CoV-2 infection, it is thought that controlling viral replication by means of SARS-CoV-2 antibody-based therapies and antiviral drugs may have the greatest impact before the host has mounted an effective immune response, whereas immune modulators may have greater efficacy later in the course of the disease when a hyperinflammatory state may predominate.
Summary of Agents
A number of agents are under evaluation for treatment and prophylaxis, but at this time only a disappointing handful are approved or convincingly shown to be of benefit.
Remdesivir is the only antiviral drug currently approved by the FDA for the treatment of COVID-19 (1). However, remdesivir requires daily intravenous administration, limiting its use to inpatient settings, and it has been found to benefit only patients who already have disease severe enough to require supplemental oxygen.
SARS-CoV-2 antibody-based therapies have been found to benefit outpatients early in the course of infection in studies of the monoclonal antibody (Mabs) bamlanivimab (also known as LY-CoV555 and LY3819253, Eli Lilly) or a combination of 2 Mabs casirivimab plus imdevimab (also called REGN-COV2, Regeneron). Both these Mab products, which are available for outpatients with COVID-19 through Emergency Use Authorizations (EUA), have been shown to lower viral load in respiratory excretions, ameliorate symptoms in outpatients who are at high risk for disease progression, and decrease hospitalizations and emergency room visits (2, 3).
Corticosteroids, specifically dexamethasone, given later in the course of COVID-19, when an exaggerated immune/inflammatory response to the infection predominates, have been found to improve survival in hospitalized patients who require supplemental oxygen, with the greatest effect observed in patients who require mechanical ventilation.
Mabs are laboratory-produced antibody proteins that are designed to bind to a specific antigenic site. Humanized Mabs are antibodies from non-human species whose protein sequences have been modified to increase their similarity to antibodies produced naturally in humans, making them less likely to be destroyed by the human body's immune system. Mabs have been successfully used to treat viral infections caused by Ebola virus and respiratory syncytial virus.
Mabs for SARS-CoV-2 bind to a specific site on the ACE2 receptor-binding region (RBD) of the spike protein on the surface of the SARS-CoV-2 virus, thus competing with the ACE2 receptor on the surface of host cells and preventing the virus from entering the host cell.
Because of the long half-life of most Mabs (about 3 weeks), a single infusion is thought to be sufficient. Mabs have the potential to be used for both prevention in people who have been exposed to someone with COVID-19 and treatment of infection in people in the earliest stages of COVID-19, before they have mounted an effective immune response. Mabs could also be used to protect older individuals and those with underlying comorbid conditions who might not be able to mount a robust protective response after vaccination. Mabs administered to nursing home residents during an outbreak might limit spread of the infection.
The NIH COVID-19 Treatment Guidelines Panel thinks the data are insufficient to recommend either for or against the use of bamlanivimab or casirivimab plus imdevimab for treatment of outpatients with mild to moderate COVID-19. Nor are there currently comparative data to determine whether there are differences in clinical efficacy or safety between bamlanivimab and casirivimab plus imdevimab (4, 5). The EUA limits use of these Mabs to outpatients with COVID-19. Patients who are hospitalized for COVID-19 should not receive bamlanivimab or casirivimab plus imdevimab outside of a clinical trial.
Plasma of people who have recovered from COVID-19 usually has antibodies that are capable of neutralizing the SARS-CoV-2 virus.
An open-label, randomized clinical trial (6) compared convalescent plasma with SARS-CoV-2 spike-receptor antibody titer greater than or equal to 1:640 with standard care in 103 hospitalized patients with severe or life-threatening COVID-19 in 7 medical centers in Wuhan, China. The study, which was terminated early due to control of the COVID-19 outbreak in Wuhan, found no significant difference between the groups in the primary outcome of time to clinical improvement within 28 days. However, the convalescent plasma was given approximately 1 month after disease onset.
Another small trial reported a benefit from convalescent plasma with a neutralizing titer dilution of greater than 1:320 in 39 hospitalized patients who did not require intubation in comparison to retrospectively matched control patients (7). As a result, the FDA authorized emergency use of convalescent plasma in patients with serious or immediately life-threatening COVID-19 infections if the patient’s physician requests a single patient emergency Investigational New Drug (IND) application (8). Over 70,000 patients in the United States received COVID-19 convalescent plasma through the Mayo Clinic’s “Expanded Access Program” (EAP), an open-label protocol that did not include an untreated control arm, primarily designed to provide adult patients who had severe or life-threatening (critical) COVID-19 access to convalescent plasma (9). The Mayo Clinic EAP was discontinued on August 28, 2020, when the FDA authorized emergency use of convalescent plasma.
In a retrospective cohort study (published in January 2021) of a subgroup of transfused hospitalized adults with COVID-19 in the Mayo Clinic EAP for whom data on antibody levels in convalescent plasma transfusions and on 30-day mortality were available, transfusion of convalescent plasma with high antibody titers was found to be more beneficial than transfusion with low-titer plasma only in patients who had not received mechanical ventilation before transfusion, particularly when the transfusion was administered within 72 hours of COVID-19 diagnosis: Of the 3,082 patients, death within 30 days after convalescent plasma transfusion occurred in 115 of 515 patients (22.3%) in the high-titer group, 549 of 2006 patients (27.4%) in the medium-titer group, and 166 of 561 patients (29.6%) in the low-titer group (10). However, the NIH COVID-19 Treatment Guidelines Panel, last updated October 9, 2020, found the data were insufficient to recommend either for or against the use of COVID-19 convalescent plasma for the treatment of COVID-19 (11).
Based on the results of clinical research from the Mayo Clinic expanded access protocol, as well as other smaller trials, the FDA updated the emergency use authorization (EUA) on February 4, 2021: only high-titer convalescent plasma should be used, and only for hospitalized patients early in the disease course and for those with impaired humoral immunity who cannot produce an adequate endogenous antibody response. Low-titer convalescent plasma is no longer authorized for use
Remdesivir: Remdesivir is an adenosine nucleoside analog that is administered intravenously as a prodrug, to which the host cell is more permeable (12). The prodrug is converted within the host cell to the active metabolite that interferes with RNA-dependent RNA polymerase (an enzyme that catalyzes the replication of RNA from an RNA template), thereby stopping virus replication. Remdesivir, which has been shown to inhibit SARS-CoV-2 in vitro and in animal models, was the first drug to get emergency authorization from the FDA for use in COVID-19 on May 1, 2020. The results of several clinical trials assessing the effectiveness of remdesivir in COVID-19 have been published in peer-reviewed medical journals.
The first of these clinical trials was published in the Lancet on May 16, 2020 (13). This randomized, double-blind, placebo-controlled clinical trial in adults hospitalized in Wuhan, China with severe COVID-19 pneumonia and hypoxia while breathing room air was terminated before attaining the prespecified sample size because the COVID-19 outbreak in China had been brought under control. No statistically significant benefits were observed for remdesivir treatment (200 mg IV on day 1 followed by 100 mg on days 2 to 10 in single daily infusions in 150 patients) beyond those of standard of care treatment in 76 patients. However, the primary endpoint of time to clinical improvement was numerically shorter in the remdesivir group than in the control group, particularly in patients treated within 10 days of symptom onset. The duration of invasive mechanical ventilation, although not significantly different between groups, was also numerically shorter in remdesivir recipients than in the control group. The investigators suggested that future studies should include earlier treatment, higher-dosing regimens of remdesivir, and remdesivir combined with other antiviral drugs or with SARS-CoV-2 neutralizing antibodies in patients with severe COVID-19 to better understand remdesivir’s potential effectiveness.
The next study, done at multiple international sites, was also a randomized, double-blind, placebo-controlled clinical trial of remdesivir (200 mg IV loading dose on day 1, followed by 100 mg daily for up to 9 additional days); it appeared in the New England Journal of Medicine on May 22, 2020 (14). In this trial in adults hospitalized with COVID-19 and lower respiratory tract involvement, the 538 patients who received remdesivir recovered 4 days faster (11 days) than the 521 who received placebo (15 days; P < 0.001). Recovery was defined by either discharge from the hospital or hospitalization for infection-control purposes only. The shorter time to recovery led the data and safety monitoring board to recommend early unblinding of the data to study team members from the National Institute of Allergy and Infectious Diseases because of its potential clinical benefits. The shorter time to recovery was most apparent in patients with moderate disease (receiving low-flow oxygen). No benefit was seen in patients with more severe disease, ie, those who required high-flow oxygen or noninvasive ventilation, mechanical ventilation, or ECMO at study enrollment, but the study was not powered to detect differences within subgroups. The median time to recovery in those who did not require supplemental oxygen was similar in the remdesivir (5 days) and placebo (6 days) groups. In terms of mortality at 14 days, 7.1% of patients taking remdesivir died and 11.9% of those given placebo died, a difference that was not statistically significant. However, a subsequent analysis based on additional data found a significant reduction of 62% (7.6 % mortality rate at day 14 for patients treated with remdesivir compared with 12.5 % in controls; P < 0.001—15).
Another study compared the outcome for 5 days (200 patients) versus 10 days (197 patients) of remdesivir therapy in hospitalized patients with COVID-19 who had radiologic evidence of pneumonia and were hypoxic while breathing room air but did not require mechanical ventilation or ECMO (16). However, the 10-day treatment group had greater disease severity at baseline than the 5-day treatment group; more patients were on mechanical ventilation prior to initiation of treatment in the 10-day than in the 5-day group. After adjustment for baseline clinical status, clinical improvement occurred by day 14 in 64% of patients in the 5-day group and in 54% in the 10-day group.
The NIH COVID-19 Treatment Guidelines Panel says there are insufficient data for or against use of remdesivir in hospitalized patients who do not require supplemental oxygen, but say that its use may be appropriate if these patients are at high risk for disease progression (1). The NIH Panel recommends use of remdesivir alone in hospitalized COVID-19 patients requiring minimal supplemental oxygen (eg, through a nasal cannula). If these patients require increasing amounts of oxygen and for patients who require oxygen through a high-flow device or noninvasive ventilation, remdesivir plus dexamethasone is recommended (1). In hospitalized patients requiring invasive mechanical ventilation or ECMO, dexamethasone alone is recommended, but remdesivir plus dexamethasone may be considered for patients who have recently been intubated (1).
The recommended duration of remdesivir treatment for patients not requiring invasive mechanical ventilation and/or ECMO is 5 days; if a patient does not demonstrate clinical improvement, treatment may be extended for up to 10 days (1, 17). The recommended total treatment duration for patients requiring invasive mechanical ventilation and/or ECMO is 10 days (1).
A randomized, placebo-controlled clinical trial is currently evaluating a nebulized, inhaled version of remdesivir in adults aged 18 to 45 years in the US to treat COVID-19 in the outpatient setting when the infection is in an early stage, thereby aborting progression to a more severe stage that would require hospitalization. An inhaled formulation of remdesivir will also deliver the drug directly to the primary sites of SARS-CoV-2 infection in the upper and lower respiratory tract (18). However, it should be noted that in the previous clinical trial, intravenous remdesivir did not shorten the time to recovery in patients who did not require supplemental oxygen. In these patients, time to recovery was similar in the remdesivir (5 days) and placebo (6 days) groups. Therefore, it is not clear whether nebulized remdesivir will work in very early infection.
Other Antiviral drugs: Favipiravir is a guanosine nucleoside analogue that selectively inhibits RNA-dependent RNA polymerase. It is a prodrug that is metabolized within host cells to its active triphosphate that inhibits viral replication. The drug is available for oral and intravenous administration and is approved for the treatment of influenza in Japan. It is being marketed for the treatment of COVID-19 in China, India, and Russia, and is undergoing clinical trials in the US. Having an oral antiviral drug, like favipiravir, could allow outpatient therapy at an early stage when the infection is not severe enough to require hospitalization if randomized controlled clinical trials show efficacy.
Ivermectin, a drug that is used to treat several parasitic infections (including onchocerciasis, helminthiases, and scabies), has been shown to have broad-spectrum antiviral activity in vitro, inhibiting the replication of SARS-CoV-2, dengue, Zika, HIV, and yellow fever in cell cultures. However, pharmacokinetic and pharmacodynamic studies suggest that achieving the plasma concentrations necessary for SARS-CoV-2 antiviral activity would require administration of doses up to 100-fold higher than those approved for use in humans. Ivermectin has not been approved for the treatment of any viral infection, including SARS-CoV-2 infection. Because randomized clinical trials and retrospective cohort studies of ivermectin use in patients with COVID-19 that have been published have significant methodological limitations, the NIH COVID-19 Treatment Guidelines Panel recommends against the use of ivermectin for the treatment of COVID-19, except in a clinical trial (19). The FDA issued a warning in April 2020 that ivermectin intended for use in animals should not be used to treat COVID-19 in humans (20).
Lopinavir and ritonavir, a combination approved to treat HIV/AIDS, has been shown to inhibit replication of SARS-CoV-2 in vitro, but plasma drug concentrations achieved using typical doses of lopinavir/ritonavir are far below the levels that may be needed to inhibit SARS-CoV-2 replication (21) and his combination failed in clinical trials (22). Similarly, darunavir/cobicistat, another a combination approved to treat HIV/AIDS, was not effective for the treatment of COVID-19 (23). In early July, the World Health Organization suspended trials of lopinavir/ritonavir on patients hospitalized for COVID-19. The NIH COVID-19 treatment guidelines recommend against using lopinavir/ritonavir or other HIV protease inhibitors for the treatment of COVID-19, except in a clinical trial (24).
Chloroquine and a less toxic version, hydroxychloroquine (HCQ), can inhibit SARS-CoV-2 from replicating in cells in vitro, but HCQ failed to prevent infection in monkeys, and, HCQ, either alone or in combination with azithromycin, failed to treat infected monkeys (25). HCQ also failed in a randomized clinical trial to treat early COVID-19 in outpatients (26) and failed to treat COVID-19 in hospitalized patients (27); it has also been found harmful in these patients (28).
The World Health Organization (29) and the NIH (30) halted trials of HCQ as a treatment for COVID-19. The US Food and Drug Administration (FDA) revoked emergency approvals for both chloroquine and HCQ, warning that the drugs can cause serious side effects to the heart and other organs when used to treat COVID-19 (31). The NIH COVID-19 Treatment Guidelines Panel recommends against using chloroquine or HCQ with or without azithromycin for the treatment of COVID-19 in both non-hospitalized and hospitalized patients, except in a clinical trial, and the Panel recommends against the use of high-dose chloroquine (600 mg twice daily for 10 days) for the treatment of COVID-19 (32).
Recombinant angiotensin-converting enzyme 2 (ACE2): Human, soluble, recombinant ACE2 protein created in the laboratory might be able to bind to SARS-CoV-2 before it can attach to host cell-bound ACE2 protein, reducing the amount of virus available to infect vulnerable host cells. Human, soluble recombinant ACE2 has been tested in phase 1 and phase 2 clinical trials in acute respiratory distress syndrome (33, 34) and can inhibit SARS-CoV-2 infection of human cells, as well as blood vessel and kidney “organoids” in vitro (35). Although human recombinant soluble ACE2 has not yet been tested in animal models, the first patient with a severe form of COVID-19 was reported to have been “successfully” treated with human recombinant soluble ACE2 (36).
Corticosteroids: Drs. Lane and Fauci point out in an editorial in the New England Journal of Medicine that an immunosuppressive drug, such as dexamethasone, or other immune modulators may be more efficacious later in the course of SARS-CoV-2 infection, when viral load has fallen and immune and inflammatory responses may be the main drivers of disease (37).
In mid-June 2020, a beneficial effect was reported for a 6-day course of methylprednisolone in 56 adults with hypoxic COVID-19 pneumonia and biochemical evidence of hyperinflammation (38). A month later, a much larger study from the Randomised Evaluation of COVID-19 Therapy (RECOVERY) Collaborative Group at Oxford University was published in the New England Journal of Medicine. In this study, British patients hospitalized with COVID-19 were randomized to receive either oral or IV dexamethasone, 6 mg/day for up to 10 days (2,104 patients) or usual care (4,321 patients—39). A beneficial effect of dexamethasone occurred in the group receiving invasive mechanical ventilation (mortality 29.3% vs 41.4%) and in the group receiving oxygen without invasive mechanical ventilation (23.3% vs 26.2%), but not in the group receiving no respiratory support at randomization (17.8% vs. 14.0%). The use of dexamethasone alone has been endorsed by the NIH COVID-19 Treatment Guidelines Panel for 10 days or until hospital discharge for the treatment of COVID-19 in hospitalized patients who require mechanical ventilation or ECMO (1). Dexamethasone combined with remdesivir is recommended for hospitalized patients receiving minimal supplemental oxygen who require increasing amounts of supplemental nasal oxygen, oxygen delivery through a high-flow device, or non-invasive ventilation, and may be considered in patients who have recently been intubated (1).
If dexamethasone is not available, alternative glucocorticoids such as prednisone, methylprednisolone, or hydrocortisone may be used. The Panel recommends against using dexamethasone for COVID-19 patients who are not hospitalized or are hospitalized but do not require supplemental oxygen.
Interferons are a family of cytokines with antiviral properties. In a double-blind, placebo-controlled trial, inhaled interferon beta-1a was found to be beneficial in nonventilated patients hospitalized with COVID-19 (40), and an open-label, randomized clinical trial did not find subcutaneous interferon beta-1a to be beneficial in patients with severe COVID-19 (41). The NIH COVID-19 Treatment Guidelines Panel recommends against the use of interferons for the treatment of patients with severe or critical COVID-19, except in a clinical trial (42).
Cytokine Inhibitors: Cytokines are proteins produced by certain cells that signal a coordinated immunologic response to infection, inflammation, and trauma. SARS-CoV-2 infection can induce a hyper-inflammatory response (eg, D-dimer > 10 times normal values, C reactive protein (CRP) > 10x normal values and/or ferritin ≥ 1000 ng/mL), with high serum levels of proinflammatory cytokines (eg, interferon gamma [IFNγ], tumor necrosis factor alpha [TNFα], interleukin 1 beta [IL-1β], and interleukin 6 [IL-6]), all of which have been associated with disease severity and death. Several drugs that target cytokines, including siltuximab, tocilizumab, sarilumab, anakinra, Janus kinase (JAK) inhibitors (eg, baricitinib), and Bruton’s tyrosine kinase (BTK) inhibitors, have been proposed for treating COVID-19.
Siltuximab is a recombinant human-mouse chimeric monoclonal antibody that binds to IL-6, blocking the binding of IL-6 to IL-6 receptors. Tocilizumab and sarilumab are recombinant humanized monoclonal antibodies that target the interleukin-6 receptor (IL-6R), blocking IL-6 from exerting its pro-inflammatory effects. Anakinra is recombinant and slightly modified version of the human interleukin 1 receptor antagonist (IL-1Ra). Anakinra blocks the biological activity of IL-1 by competitively inhibiting IL-1 from binding to the interleukin-1 type I receptor. Baricitinib, a Janus kinase (JAK) inhibitor, blocks the intracellular signaling pathway for proinflammatory cytokines. Bruton’s tyrosine kinase (BTK) inhibitors block cytokine signaling through the B-cell surface receptors necessary for B-cell trafficking, chemotaxis, and adhesion.
Tocilizumab: A press release on February 11, 2021, reported the preliminary results of a Randomised Evaluation of COVID-19 Therapy (RECOVERY) trial, in which more than 4,000 patients hospitalized with severe COVID-19 (required oxygen and had evidence of inflammation) were randomized to receive either tocilizumab or the usual care (82% of patients in both groups were also treated with a systemic corticosteroid, such as dexamethasone---43). This RECOVERY trial found that tocilizumab had a slight, but statistically significant, mortality benefit in combination with a corticosteroid; 29% of tocilizumab-treated patients with died within 28 days versus 33% of patients treated with usual care (P = 0.007). Tocilizumab reduced the chance of progressing to invasive mechanical ventilation from 38% to 33% (P = 0·0005) and shortened the time to discharge. These benefits occurred in all patient subgroups, including those requiring oxygen via a face mask through to those requiring mechanical ventilation. However, tocilizumab did not reduce the time on invasive mechanical ventilation. There are limited published data describing the efficacy of siltuximab, sarilumab, and anakinra in patients with COVID-19. The NIH Panel, dated August 27, 2020, prior to release of the results of the RECOVERY tocilizumab trial, recommends against the use of anti-IL-6 receptor monoclonal antibodies (eg, sarilumab, tocilizumab) or anti-IL-6 monoclonal antibody (siltuximab) for the treatment of COVID-19, except in a clinical trial (44) and the NIH Panel says the data are insufficient to recommend for or against the use of interleukin (IL)-1 inhibitors, such as anakinra, for the treatment of COVID-19 (45).
The NIH COVID-19 Treatment Guidelines Panel recommends against the use of Bruton’s tyrosine kinase (BTK) inhibitors, such as acalabrutinib, ibrutinib, and zanubrutinib; and the Janus kinase (JAK) inhibitors, such as ruxolitinib and tofacitinib; for the treatment of COVID-19, except in a clinical trial (46).
Baricitinib: In a randomized controlled clinical trial, in which hospitalized patients with COVID-19 and evidence of pneumonia received either baricitinib, a JAK inhibitor, or placebo (with both groups receiving remdesivir), the combination of baricitinib and remdesivir was associated with a shorter time to recover, as well as faster improvement in clinical status, as compared with the placebo group, especially among those receiving high-flow oxygen or noninvasive ventilation (47). Baricitinib was issued an Emergency Use Authorization (EUA) for the combination of baricitinib with remdesivir in hospitalized adults and children aged ≥ 2 years with COVID-19 who require supplemental oxygen, invasive mechanical ventilation, or extracorporeal membrane oxygenation (ECMO), an indication similar to that of corticosteroids +/- remdesivir. The NIH COVID-19 Treatment Guidelines Panel thought data was insufficient to recommend either for or against the use of baricitinib in combination with remdesivir in cases where corticosteroids can be used instead. In the rare circumstances where corticosteroids cannot be used instead, the NIH Panel recommends using baricitinib in combination with remdesivir for the treatment of COVID-19 in hospitalized, nonintubated patients who require oxygen supplementation (48). The Panel recommends against the use of baricitinib in the absence of remdesivir, except in a clinical trial. There are insufficient data for the Panel to recommend either for or against the use of baricitinib in combination with corticosteroids for the treatment of COVID-19. Since both agents are potent immunosuppressants, there is potential for an additive risk of infection.
Antithrombotic Therapy in Patients with COVID-19
A hypercoagulable state may complicate the course of COVID-19. Venous complications include deep venous thrombosis (DVT) and pulmonary emboli (PE). Arterial complications include thrombosis that may cause ischemic strokes, limb ischemia, or myocardial infarction. Microvascular thrombosis in the lungs impairs oxygen exchange. Older age, male sex, obesity, cancer, history of venous thromboembolism (VTE), or comorbid diseases in patients with severe COVID-19 carry higher risk of DVT and PE than mild or asymptomatic disease.
Because increased bleeding is a known complication of full-dose anticoagulation, a large, multinational clinical trial of adults hospitalized for COVID-19 compared use of full anticoagulant doses to a lower dose regimen such as that used to prevent blood clots in hospitalized patients. One group consisted of patients with non-ICU hospital care and another of critically ill patients requiring ICU care at enrollment. ICU level of care was defined as requiring high flow nasal oxygen, invasive or noninvasive mechanical ventilation, vasopressor therapy, or extracorporeal membrane oxygenation (ECMO) support.
On December 21, 2020, the part of the clinical trial that involved patients with severe COVID-19 requiring ICU level of care at enrollment was paused because interim analysis found that higher, therapeutic doses of anticoagulation drugs did not reduce the need for organ support and mortality, compared to lower, prophylactic dosed anticoagulation (49). Patients who did not require ICU care at the time of enrollment continued to be enrolled in the trial.
On January 22, 2021, based on the interim results of the large clinical trial conducted worldwide in more than 1,000 moderately ill, non-ICU hospitalized patients, full doses of heparin, in addition to being safe, were superior to the doses normally given to prevent blood clots in hospitalized patients—with regard to reduced requirement for vital organ support, defined as number of hospital days not requiring high-flow nasal oxygen, invasive or noninvasive mechanical ventilation, vasopressor therapy, or ECMO support and in-hospital mortality (50). A trend in possible reduction of mortality was also observed and is being further studied.
The latest NIH COVID-19 Treatment Guidelines Panel on antithrombotic therapy in patients with COVID-19 says currently there are insufficient data to recommend either for or against the use of thrombolytics or higher than the prophylactic dose of anticoagulation for VTE prophylaxis in hospitalized COVID-19 patients outside of a clinical trial. However, the NIH Panel Guidelines is dated December 17, 2020, before the interim results of the clinical trials on optimal anticoagulant dosing to reduce thrombotic complications in non-ICU and ICU hospitalized patients with COVID-19 (see above), and their recommendations may not reflect these findings (51).
The NIH Panel recommends also the following:
1. COVID-19 Treatment Guidelines Panel. Coronavirus Disease 2019 (COVID-19) Treatment Guidelines. National Institutes of Health. Available at https://www.covid19treatmentguidelines.nih.gov/therapeutic-management/ Accessed January 29, 2021.
2. US Food and Drug Administration: Fact Sheet for Health Care Providers Emergency Use Authorization of casirivimab and imdevimab. Available at https://www.fda.gov/media/143892/download
3. Chen P, Nirula A, Heller B, et al: SARS-CoV-2 neutralizing antibody LY-CoV555 in outpatients with COVID-19. New Engl J Med 384(3):229-237, 2021. doi: 10.1056/NEJMoa2029849 https://pubmed.ncbi.nlm.nih.gov/33113295/
4. COVID-19 Treatment Guidelines Panel. Coronavirus Disease 2019 (COVID-19) Treatment Guidelines. National Institutes of Health. Available at https://www.covid19treatmentguidelines.nih.gov/statement-on-casirivimab-plus-imdevimab-eua/. Accessed January 29, 2021.
5. COVID-19 Treatment Guidelines Panel. Coronavirus Disease 2019 (COVID-19) Treatment Guidelines. National Institutes of Health. Available at https://www.covid19treatmentguidelines.nih.gov/statement-on-bamlanivimab-eua/ Accessed January 29, 2021.
6. Li L, Zhang W, Hu Y: Effect of convalescent plasma therapy on time to clinical improvement in patients with severe and life-threatening Covid-19. JAMA June 3, 2020. Accessed July 27, 2020. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7270883/
7. Liu STH, Lin H-M, Baine I, et al: Convalescent plasma treatment of severe COVID-19: A matched control study. medRxiv PREPRINT May 22, 2020. Accessed July 29, 2020. https://www.medrxiv.org/content/10.1101/2020.05.20.20102236v1
8. Recommendations for investigational COVID-19 convalescent plasma. May 1, 2020. Available at https://www.fda.gov/vaccines-blood-biologics/investigational-new-drug-ind-or-device-exemption-ide-process-cber/recommendations-investigational-covid-19-convalescent-plasma#Pathways%20for. Accessed July 28, 2020.
9. Covid-19 Expanded Access Program. Available at https://www.uscovidplasma.org. Accessed July 30, 2020.
10. Joyner MJ, Carter RE, Senefeld, JW, et al. Convalescent Plasma Antibody Levels and the Risk of Death from Covid-19. N Engl J Med January 13, 2021 doi: 10.1056/NEJMoa2031893 https://www.nejm.org/doi/full/10.1056/NEJMoa2031893
11. COVID-19 Treatment Guidelines Panel. Coronavirus Disease 2019 (COVID-19) Treatment Guidelines. National Institutes of Health. Available at https://www.covid19treatmentguidelines.nih.gov/immune-based-therapy/blood-derived-products/convalescent-plasma/ Accessed January 29, 2021.
12. Eastman RT, Roth JS, Brimacombe KR, et al: Remdesivir: a review of its discovery and development leading to emergency use authorization for treatment of COVID-19. ACS Cent Sci 6(6):1009, 2020. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7202249/
13. Wang Y, Zhang D, Du G, et al: Remdesivir in adults with severe COVID-19: a randomized, double-blind, placebo-controlled mutlicentre trial. Lancet 395:1569–1578, 2020.
14. Beigel JR, Tomashek KM, Dodd LE, et al: Remdesivir for the treatment of Covid-19---Preliminary report. N Engl J Med May 22, 2020. https://www.nejm.org/doi/full/10.1056/NEJMoa2007764
15. Gilead presents additional data on investigational antiviral remdesivir for the treatment of Covid-19. News release. Gilead Sciences July 10, 2020. Available at https://www.gilead.com/news-and-press/press-room/press-releases/2020/7/gilead-presents-additional-data-on-investigational-antiviral-remdesivir-for-the-treatment-of-covid-19. Accessed July 29, 2020.
16. Goldman JD, Lye DCB, Hui DS, et al: Remdesivir for 5 or 10 days in patients with severe covid-19. N Engl J Med May 27, 2020. https://www.nejm.org/doi/full/10.1056/NEJMoa2015301
17. Veklury [package insert] Gilead Sciences, Inc, 2020. https://www.vekluryhcp.com/?gclid=CjwKCAiAu8SABhAxEiwAsodSZG91PDQt61aoVCtUgyBtGduqIQmYqq4SEoh5HDlJ49Mp5qvI-GXHJhoC874QAvD_BwE&gclsrc=aw.ds
18. Clinical Trials Arena: Gilead begins testing of inhaled version of remdesivir for Covid-19. Clinical Trials Arena July 9, 2020. Available at https://www.clinicaltrialsarena.com/news/gilead-inhaled-remdesivir-phasei/. Accessed July 29, 2020.
19. COVID-19 Treatment Guidelines Panel. Coronavirus Disease 2019 (COVID-19) Treatment Guidelines. National Institutes of Health. Available at https://www.covid19treatmentguidelines.nih.gov/antiviral-therapy/ivermectin/
20. FDA Letter to Stakeholders: Do not use ivermectin intended for animals as treatment for COVID-19 in humans. April 10, 2020. https://www.fda.gov/animal-veterinary/product-safety-information/fda-letter-stakeholders-do-not-use-ivermectin-intended-animals-treatment-covid-19-humans
21. Schoergenhofer C, Jilma B, Stimpfl T, Karolyi M, Zoufaly A. Pharmacokinetics of lopinavir and ritonavir in patients hospitalized with coronavirus disease 2019 (COVID-19). Ann Intern Med 2020. https://www.ncbi.nlm.nih.gov/pubmed/32422065
22. Cao B, Wang Y, Wen D, et al. A trial of lopinavir-ritonavir in adults hospitalized with severe COVID-19. N Engl J Med 2020;382(19):1787-1799. https://www.ncbi.nlm.nih.gov/pubmed/32187464
23. Chen J, Xia L, Liu L, et al. Antiviral activity and safety of darunavir/cobicistat for the treatment of COVID-19. Open Forum Infect Dis 2020. https://www.ncbi.nlm.nih.gov/pubmed/32671131
24. COVID-19 Treatment Guidelines Panel. Coronavirus Disease 2019 (COVID-19) Treatment Guidelines. National Institutes of Health. Available at https://www.covid19treatmentguidelines.nih.gov/antiviral-therapy/lopinavir-ritonavir-and-other-hiv-protease-inhibitors/
25. Maisonnasse P, Guedj J, Contreras V, et al: Hydroxychloroquine use against SARS-CoV-2 infection in non-human primates. Nature July 22, 2020. https://www.nature.com/articles/s41586-020-2558-4
26. Skipper CP, Pastick KA, Engen NW, et al: Hydroxychloroquine in nonhospitalized adults with early Covid-19. Ann Intern Med July 16, 2020. https://www.acpjournals.org/doi/10.7326/M20-4207
27. Horby P, Landray M: No clinical benefit from use of hydroxychloroquine in hospitalised patients with covid-19. Statement from the Chief investigators of the Randomised Evaluation of COVid-19 thERaPY (RECOVERY) Trial on Hydroxychloroquine. June 5, 2020. Available at https://www.recoverytrial.net/news/statement-from-the-chief-investigators-of-the-randomised-evaluation-of-covid-19-therapy-recovery-trial-on-hydroxychloroquine-5-june-2020-no-clinical-benefit-from-use-of-hydroxychloroquine-in-hospitalised-patients-with-covid-19 Accessed July 30,2020.
28. Magagnoli J, Narendran S, Pereria F, et al: Outcomes of hydroxychloroquine usage in United States veterans hospitalized with Covid-19. Med (New York, NY) June 5, 2020 epub ahead of print https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7274588/
29. WHO discontinues hydroxychloroquine and lopinavir/ritonavir treatment arms for Covid-19. News release July 4, 2020. Available at https://www.who.int/news-room/detail/04-07-2020-who-discontinues-hydroxychloroquine-and-lopinavir-ritonavir-treatment-arms-for-covid-19. Accessed July 29, 2020.
30. NIH halts clinical trial of hydroxychloroquine. News release. June 20, 2020. Available at https://www.nih.gov/news-events/news-releases/nih-halts-clinical-trial-hydroxychloroquine. Accessed July 29, 2020.
31. FDA: Hinton DM to Disbrow GL. Letter revoking EUA for chloroquine phosphate and hydroxychloroquine sulfate. June 15, 2020. Available at https://www.fda.gov/media/138945/download. Accessed July 29, 2020.
32. COVID-19 Treatment Guidelines Panel. Coronavirus Disease 2019 (COVID-19) Treatment Guidelines. National Institutes of Health. Available at https://www.covid19treatmentguidelines.nih.gov/antiviral-therapy/chloroquine-or-hydroxychloroquine-with-or-without-azithromycin/
33. Haschke M, Schuster M, Poglitsch M, et al: Pharmacokinetics and pharmacodynamics of recombinant human angiotensin-converting enzyme 2 in healthy human subjects. Clin Pharmacokinet 52:783-792, 2013. https://pubmed.ncbi.nlm.nih.gov/23681967/
34. Khan A, Benthin C, Zeno B, et al: A pilot clinical trial of recombinant human angiotensin-converting enzyme 2 in acute respiratory distress syndrome. Crit Care 21:234, 2017. https://ccforum.biomedcentral.com/articles/10.1186/s13054-017-1823-x
35. Monteil V, Kwon H, Prado P, et al: Inhibition of SARS-CoV-2 infection in engineered human tissues using clinical-grade soluble human ACE2. Cell 181(4):905-913.e7,2020. doi: 10.1016/j.cell.2020.04.004 https://pubmed.ncbi.nlm.nih.gov/32333836/
36 Zoufaly A, Poglitsch M, Aberle JH, et al: Human recombinant soluble ACE2 in severe COVID-19. Lancet: Respiratory Medicine 11(8): P1154-P1158, 2020. https://pubmed.ncbi.nlm.nih.gov/33131609/
37. Lane HC, Fauci AS: Research in the context of a pandemic. N Engl J Med July 17, 2020. https://www.nejm.org/doi/full/10.1056/NEJMe2024638?query=recirc_curatedRelated_article
38. Corral L, Bahamonde A, Arnaiz de las Revillas F, et al: GLUCOCOVID: A controlled trial of methylprednisolone in adults hospitalized with COVID-19 pneumonia. medRxiv PREPRINT posted online June 18, 2020. doi: https://doi.org/10.1101/2020.06.17.20133579https://www.medrxiv.org/content/10.1101/2020.06.17.20133579v1
39. The RECOVERY Collaborative Group: Dexamethasone in hospitalized patients with Covid-19---Preliminary report. N Engl J Med July 17, 2020. https://www.nejm.org/doi/full/10.1056/NEJMoa2021436
40. Synairgen announces positive results from trial of SNG001 in hospitalised COVID-19 patients [press release]. July 20, 2020. Available at: https://www.synairgen.com/wp-content/uploads/2020/07/200720-Synairgen-announces-positive-results-from-trial-of-SNG001-in-hospitalised-COVID-19-patients.pdf. Accessed August 24, 2020
41. Davoudi-Monfared E, Rahmani H, Khalili H, et al. A randomized clinical trial of the efficacy and safety of interferon beta-1a in treatment of severe COVID-19. Antimicrob Agents Chemother 2020;64(9):e01061-20. https://www.ncbi.nlm.nih.gov/pubmed/32661006
42. COVID-19 Treatment Guidelines Panel. Coronavirus Disease 2019 (COVID-19) Treatment Guidelines. National Institutes of Health. Last Updated: August 27, 2020 https://www.covid19treatmentguidelines.nih.gov/immune-based-therapy/immunomodulators/interferons/
43. Tocilizumab reduces deaths in patients hospitalised with Covid-19. Recovery: Randomised evaluation of COVID-19 Therapy. February 11, 2021. Available at https://www.recoverytrial.net/news/tocilizumab-reduces-deaths-in-patients-hospitalised-with-covid-19. Accessed February 14, 2021.
44. COVID-19 Treatment Guidelines Panel. Coronavirus Disease 2019 (COVID-19) Treatment Guidelines. National Institutes of Health. Last Updated: August 27, 2020 https://www.covid19treatmentguidelines.nih.gov/immune-based-therapy/immunomodulators/interleukin-6-inhibitors/
45. COVID-19 Treatment Guidelines Panel. Coronavirus Disease 2019 (COVID-19) Treatment Guidelines. National Institutes of Health. Last Updated: July 17, 2020 https://www.covid19treatmentguidelines.nih.gov/immune-based-therapy/immunomodulators/interleukin-1-inhibitors/
46. COVID-19 Treatment Guidelines Panel. Coronavirus Disease 2019 (COVID-19) Treatment Guidelines. National Institutes of Health. Last Updated: July 17, 2020 https://www.covid19treatmentguidelines.nih.gov/immune-based-therapy/immunomodulators/kinase-inhibitors/
47. Kalil AC, Patterson TF, Mehta AK, et al. Baricitinib plus Remdesivir for Hospitalized Adults with Covid-19. N Engl J Med 2020 Dec 11 https://www.nejm.org/doi/10.1056/NEJMoa2031994
48. COVID-19 Treatment Guidelines Panel. Coronavirus Disease 2019 (COVID-19) Treatment Guidelines. National Institutes of Health. Available at https://www.covid19treatmentguidelines.nih.gov/statement-on-baricitinib-eua/
49. NIH ACTIV trial of blood thinners pauses enrollment of critically ill COVID-19 patients. News release NIH. December 22, 2020. Available at https://www.nih.gov/news-events/news-releases/nih-activ-trial-blood-thinners-pauses-enrollment-critically-ill-covid-19-patients. Accessed February 24, 2021.
50. Full-dose blood thinners decreased need for life support and improved outcome in hospitalized COVID-19 patients. News release. NIH. January 21, 2021. Available at https://www.nih.gov/news-events/news-releases/full-dose-blood-thinners-decreased-need-life-support-improved-outcome-hospitalized-covid-19-patients. Accessed February 24, 2020.
51. COVID-19 Treatment Guidelines Panel. Coronavirus Disease 2019 (COVID-19) Treatment Guidelines. Antithrombotic Therapy. National Institutes of Health. February 11, 2021. Available at https://www.covid19treatmentguidelines.nih.gov/adjunctive-therapy/antithrombotic-therapy/