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November 11, 2020

Therapy for Early COVID-19: A Critical Need

Author Affiliations
  • 1Division of AIDS, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland
  • 2National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland
JAMA. 2020;324(21):2149-2150. doi:10.1001/jama.2020.22813

While coronavirus disease 2019 (COVID-19) is predominantly self-limited, up to 20% of symptomatic individuals will progress to severe or critical disease with clinical manifestations including pneumonia, acute respiratory distress syndrome, multiorgan system dysfunction, hypercoagulation, and hyperinflammatory manifestations. There have been more than 47 million cases of COVID-19 globally resulting in more than 1.2 million deaths. Additionally, a growing body of data suggests that some patients with COVID-19, including individuals with mild symptoms, will have a variably prolonged course of recovery including fatigue, cognitive impairment, and cardiopulmonary dysfunction.1 While treatment options for patients with severe disease requiring hospitalization are now available, with corticosteroids emerging as the treatment of choice for critically ill patients, interventions that can be administered early during the course of infection to prevent disease progression and longer-term complications are urgently needed.2,3

Recent attention has been focused on the potential of early treatment for individuals with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection at high risk for serious outcomes. Yet, there is a noteworthy absence of treatments proven to be efficacious for patients with early or mild infection. Immediate benefits of such treatments include improvement of patient outcomes and prevention of hospitalizations. Longer-term benefits may include prevention of the chronic sequelae of infection as well as prevention of transmission by shortening the period of infectiousness. Outpatient treatments for COVID-19, coupled with an effective vaccine, would have significant implications for the ability to end this pandemic.

Recent successes in the development of effective treatments for moderately to severely ill hospitalized patients have been reported. The Adaptive COVID-19 Treatment Trial (ACTT), a phase 3, randomized, placebo-controlled trial, demonstrated that the antiviral agent remdesivir was effective in reducing time to recovery in adults hospitalized with COVID-19.4 These findings helped to support Food and Drug Administration approval for use of remdesivir in hospitalized patients. Additionally, the RECOVERY trial, a large, adaptive trial designed to evaluate efficacy of several therapeutic interventions, compared with standard of care, revealed that dexamethasone reduced mortality in hospitalized patients requiring mechanical ventilation or high-flow oxygen.5 Both remdesivir and dexamethasone have now been endorsed globally by multiple COVID-19 treatment guideline committees and have led to improvements in patient outcomes among those requiring hospitalization.

However, effective treatments for people with mild to moderate disease have been more elusive. Remdesivir requires daily infusions for up to 10 days4 and is not suitable for an ambulatory setting. Dexamethasone has not been tested in early, mild disease, but its immune-suppressive effects could potentially worsen clinical outcomes in this setting. Several drugs, such as hydroxychloroquine, have failed to show efficacy in rigorous clinical trials despite early uncontrolled studies suggesting a positive effect.6 Moreover, the risk-benefit calculus in mild to moderate disease differs from that of severe disease. Treatments for outpatients with mild disease must be safe with few adverse effects, easy to administer, and scalable. Despite these hurdles, a cadre of new treatments has now entered the clinical development pipeline.

Several antivirals approved or in development for other viral infections, such as HIV, hepatitis C virus, and ebolaviruses, are under investigation for early treatment of COVID-19. These investigations have not yet yielded clinically actionable results; however, many trials are ongoing. Examples of antivirals in trials for early treatment of COVID-19 are MK-4482 (EIDD-2801), an orally bioavailable ribonucleoside inhibitor that was originally developed for influenza (NCT04575597); SNG001, a nebulized formulation of interferon-β1a developed for viral infections in patients with chronic obstructive pulmonary disease (NCT04385095); and camostat mesylate, a serine protease inhibitor approved for treatment of chronic pancreatitis and postoperative reflux esophagitis (NCT04353284).

Immune-modulating drugs are being extensively examined for treatment of moderate to severe COVID-19. Even though these agents are less likely to be as beneficial as antivirals during early infection, this approach is also being explored for early, mild disease. Additionally, approaches to prevent some of the more severe complications of COVID-19 are being tested. Several clinical trials, including the National Institutes of Health–sponsored ACTIV-4 trial (COVID-19 Positive Outpatient Thrombosis Prevention Trial [NCT04498273]) are testing factor Xa inhibitors and other anticoagulant strategies to prevent thromboembolic complications.

SARS-CoV-2–specific approaches, such as antiviral antibodies, are also being developed. Convalescent plasma, hyperimmune γ-globulin, and polyclonal antibody products are being tested in a wide range of studies including in participants with mild to moderate disease. Additionally, monoclonal antibodies are in development by several companies and academic investigators. Early-phase clinical trials sponsored by Eli Lilly (Ly-CoV555) and Regeneron (REGN-COV2) have yielded promising results suggesting that monoclonal antibodies may be effective in decreasing viremia and improving clinical outcomes in patients with early COVID-19.7,8 Although these initial monoclonal antibody interventions are administered intravenously and, therefore, present challenges for the outpatient setting, alternative routes of administration, such as inhalation and subcutaneous or intramuscular injection, are also being developed and would be more practical for use in early disease.

Given the duration and severity of the COVID-19 pandemic, investments into targeted de novo drug design approaches for early treatment are also warranted. Although this effort will be lengthy and more costly than repurposing, discovery of novel targeted antivirals may prove useful not only for COVID-19, but also in future pandemics. Lessons can be drawn from successful development of antivirals against other viruses such as HIV and hepatitis C. As with those viruses, combinations of antivirals may be needed for the most effective therapy and to avoid development of resistance.

While the current pipeline of treatments provides hope that effective, early–COVID-19 therapeutics may soon be available, much work remains to be done. Continued research is needed to refine current treatment candidates and develop new drugs that can be dosed without requiring intravenous infusions or other complex maneuvers. Effective treatments that require infusion may be the first approved for clinical use and will have a significant public health impact. However, for the greatest benefit, treatments will need to be administered easily and made available widely at low cost.

Furthermore, rigorous clinical trials will be needed to provide the data to confidently prescribe treatments for individuals and properly implement interventional strategies at the public health level. At best, these trials are difficult to implement. They require large sample sizes and a complex infrastructure to ensure participant and staff safety. Shortages of medications, medical supplies, and staff and overburdened health systems resulting from the pandemic further amplify the challenge. To address these difficulties, and in partnership with Operation Warp Speed, the National Institutes of Health has established multiple clinical trials as part of the Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV) public-private partnership. The ACTIV-2 trial (Adaptive Platform Treatment Trial for Outpatients with COVID-19 [NCT04518410]), in particular, is a platform protocol designed to evaluate promising antivirals starting with a phase 2 trial and seamlessly progressing into a phase 3 trial for treatment of early COVID-19 in the outpatient setting. The platform design allows the pooling of resources to efficiently evaluate multiple interventions simultaneously and ensure that effective therapies are moved forward into the clinic.

From drug discovery to rigorous clinical trials, these challenges demand a significant level of commitment and effort from all parties involved including pharmaceutical companies, scientists, clinical trialists, and study volunteers. Preventing hospitalizations and the chronic sequelae of COVID-19 will not only save lives, but also will help restore medical systems and other institutions that are overburdened by the effects of the pandemic. Effective, early treatments will also mitigate gaps left by previous and current prevention strategies and curtail forward transmission. It is encouraging that effective outpatient treatments for early COVID-19 are on the horizon; these efforts deserve the full support of the medical community and the public.

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Article Information

Corresponding Author: Peter S. Kim, MD, Therapeutics Research Program, Division of AIDS, National Institute of Allergy and Infectious Diseases, National Institutes of Health, 5601 Fishers Ln, Bethesda, MD 20892 (peter.kim2@nih.gov).

Published Online: November 11, 2020. doi:10.1001/jama.2020.22813

Conflict of Interest Disclosures: Dr Kim reported serving as the National Institutes of Health (NIH) lead for the ACTIV-2 trial but has no financial relationship with the trial. No other disclosures were reported.

Additional Information: Dr Kim is Director of the Therapeutics Research Program in the Division of AIDS (DAIDS) of the National Institute of Allergy and Infectious Diseases (NIAID) at the NIH; Dr Read is Deputy Director of DAIDS; and Dr Fauci is Director, NIAID.

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Prescott  HC, Rice  TW.  Corticosteroids in COVID-19 ARDS: evidence and hope during the pandemic.   JAMA. 2020;324(13):1292-1295. doi:10.1001/jama.2020.16747PubMedGoogle ScholarCrossref
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Sterne  JAC, Murthy  S, Diaz  JV,  et al; WHO Rapid Evidence Appraisal for COVID-19 Therapies (REACT) Working Group.  Association between administration of systemic corticosteroids and mortality among critically ill patients with COVID-19: a meta-analysis.   JAMA. 2020;324(13):1330-1341. doi:10.1001/jama.2020.17023PubMedGoogle ScholarCrossref
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    5 Comments for this article
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    Treatments For Early Use
    Peter Staats, Chief Medical Officer | National Spine and Pain Centers
    I am incredibly grateful to Dr Fauci and his team for the national and world wide leadership in managing this COVID crisis and agree with the need for early (and late) interventions for patients with COVID-19. It is important to note that the FDA has authorized treatments for certain patients early in the course of the disease. It is important to consider safety and efficacy of early interventions as they may help decrease the need for hospitalization, and just maybe alter the course of the diseases. Close to a third of all patients are experiencing some type of long-term COVID symptoms. This may be due to end-organ damage from the virus itself, or more likely persistent cytokine release or the coagulation disorders that have received so much attention of late. 

    Readers might be aware that in July of this year the FDA issued an emergency use authorization (EUA) for a handheld neuromodulating vagal nerve stimulator "intended for acute use at home or in a healthcare setting to treat adult patients with known or suspected COVID-19 who are experiencing exacerbation of asthma-related dyspnea and reduced airflow, and for whom approved drug therapies are not tolerated or provide insufficient symptom relief as assessed by their healthcare provider (HCP)" (1). The EUA makes clear that the device "has neither been cleared nor approved for acute use," and that the EUA "has been authorized only for the duration of the declaration that circumstances exist justifying the authorization of the emergency use of medical devices under section 564(b)(1) of the Act, 21 U.S.C. § 360bbb-3(b)(1), unless the authorization is terminated or revoked sooner (1).

    REFERENCE

    1. https://www.fda.gov/media/139967/download
    CONFLICT OF INTEREST: CoFounder and Chief Medical Officer electroCore
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    Vitamin C in Early Covid-19
    David Smith, MA, DPhil | Department of Pharmacology, University of Oxford, UK
    The body’s status in vitamin C is drastically reduced in conditions of severe stress such as infection, trauma, and surgery. There have been two small studies in Covid-19 patients which report low levels of vitamin C (1, 2). There is evidence from other respiratory diseases that vitamin C treatment may be beneficial (3, 4) and currently there are some 30 trials in progress testing the therapeutic benefit of high dose vitamin C in late stage Covid-19 (4). In view of the urgent need pointed out by Kim et al. (5), I suggest that there is a prima facie case for a randomized trial to assess the effect of measuring vitamin C status in new Covid-19 patients.

    REFERENCES

    1. Arvinte C, Singh M, Marik PE. Serum Levels of Vitamin C and Vitamin D in a Cohort of Critically Ill COVID-19 Patients of a North American Community Hospital Intensive Care Unit in May 2020: A Pilot Study. Med Drug Discov. Dec 2020;8:100064. doi:10.1016/j.medidd.2020.100064
    2. Chiscano-Camón L, Ruiz-Rodriguez JC, Ruiz-Sanmartin A, Roca O, Ferrer R. Vitamin C levels in patients with SARS-CoV-2-associated acute respiratory distress syndrome. Crit Care. Aug 26 2020;24(1):522. doi:10.1186/s13054-020-03249-y
    3. Holford P, Carr AC, Jovic TH, et al. Vitamin C – an Adjunctive Therapy for Respiratory Infection, Sepsis and COVID-19. Nutrients. 2020;submitteddoi:10.20944/preprints202010.0407.v1
    4. Patterson G, Isales CM, Fuzele S. Low level of Vitamin C and dysregulation of Vitamin C transporter might be involved in the severity of COVID-19 Infection. Aging and disease. 2021;12(2)doi:10.14336/AD.2020.0918
    5. Kim PS, Read SW, Fauci AS. Therapy for Early COVID-19: A Critical Need. JAMA. Nov 11 2020;doi:10.1001/jama.2020.22813
    CONFLICT OF INTEREST: None Reported
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    Early Treatment of COVID-19
    Binh Ngo, M.D. | Keck USC School of Medicine
    We were pleased that JAMA published the viewpoint by Kim et al "Therapy for Early COVID-19 A Critical Need' (1). That viewpoint mirrors the opinions we express in a consensus manuscript with a group of over 30 multinational authors now up on the preprint service medRxiv (2), where it is in its 7th version.

    Our paper includes several additional suggestions, including potential issues with vaccines, use of favipiravir (now approved and utilized in several different countries), and utilization of trial data from other countries in making the decisions on treatment in the United States.

    References

    1)
    Kim PS, Read SW, Fauci AS. Therapy for Early COVID-19: A Critical Need. JAMA. Published online November 11, 2020. doi:10.1001/jama.2020.22813

    2) Binh T. Ngo, Paul Marik, Pierre Kory, Leland Shapiro, Denise Brennan-Rieder, Raphael Thomadsen, Jose Iglesias, Stephen Ditmore, Marc Rendell, Joseph Varon, Michael Dubé, Neha Nanda, Gino In, Daniel Arkfeld, Preet Chaudhary, Vito M. Campese, Diana L. Hanna, David E. Sawcer, Glenn Ehresmann, David Peng, Miroslaw Smogorewski, April Armstrong, Rajkumar Dasgupta, Fred Sattler, Cristina Mussini, Oriol Mitja, Vicente Soriano, Nicolas Peschanski, Gilles Hayem, Marco Confalonieri, Maria Carmela Piccirillo, Antonio Lobo-Ferreira, Iraldo Bello Rivero, Eivind H. Vinjevoll, Daniel Griffin, Ivan FN Hung. The Time Course of Therapeutic Interventions for Covid-19 medRxiv 2020.05.27.20115238; doi: https://doi.org/10.1101/2020.05.27.20115238

    3) Flanagin A, Fontanarosa PB, Bauchner H. Preprints Involving Medical Research—Do the Benefits Outweigh the Challenges? JAMA. 2020;324(18):1840–1843. doi:10.1001/jama.2020.20674
    CONFLICT OF INTEREST: None Reported
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    Early Prevention of Hypoxemia
    Calixto Machado, MD, PhD, FAAN | Institute of Neurology and Neurosurgery, Havana, Cuba
    I read with interest the paper of Sim et al. suggesting an early therapy of Covid-19 patients (1).

    The most awful complication in COVID-19 is hypoxemia due to respiratory failure. The mechanisms of lung damage and hypoxemia in COVID-19 include ventilation/perfusion mismatch, loss of hypoxic vasoconstriction and increased coagulopathy. A substantial proportion of patients who are admitted to intensive care units (ICUs) worsen in a short period of time and die from acute respiratory distress syndrome (ARDS) (2,3).

    Abnormal and uncontrolled production of cytokines has been observed in critically ill patients with COVID-19 pneumonia. The subsequent uncontrolled cytokine
    storm in COVID-19 patients is centrally involved in the aggravation of symptoms and disease development, and denotes a key factor contributing to ARDS and mortality (2-4).
     
    Tissue hypoxia can significantly affect the development or attenuation of inflammation by causing the regulation of hypoxia-dependent gene expression, inducing several transcription factors, which play a central role in stimulating the proinflammatory cytokines (3,5).

    The treatment for COVID-19 patients in ICUs has included early intubation and invasive ventilation, when patients have already shown signs of acute respiratory failure. Nevertheless, non-invasive ventilation (NIV) may have a more significant and helpful role than first thought. Among NIV methods, continuous positive air pressure (CPAP) is nowadays the preferred form of NIV in the management of COVID-19 patients. With commercially available CPAP equipment, there is now growing evidence that it may be of benefit to patients in the disease process, avoiding hypoxia, and then may prevent deterioration and reduce the need for invasive ventilation at all (3).

    An early use of NIV by CPAP, when patients are still outside the ICUs, i.e. in regular wards or at patient’s homes, could prevent periods of hypopnea and hypoxia which would trigger the synthesis of ACE in lung endothelial cells, finally leading to cytokine storm, ARDS, multi-organ failure, and death (3,5). Clinicians should not wait to intubate and mechanically ventilate COVID-19 patients in ICUs, when they are already suffering a severe acute respiratory failure. This early treatment intervention might reduce mortality in this terrible disease.

    References

    1. Kim P, Read S, Fauci A. Therapy for Early COVID-19: A Critical Need. JAMA. 2020. Published online November 11, 2020. doi:10.1001/jama.2020.22813.
    2. Machado C. Severe Covid-19 cases: Is respiratory distress partially explained by central nervous system involvement? . Medic Review. 2020;22(2):38-41.
    3. Machado C, Mualem R, DeFina P, et al. It Is imperative the use of positive air pressure (CPAP) in COVID-19 Patients as soon as the first respiratory symptoms start. Frontiers Journal of Neurology and Neuroscience. 2020;1(1):1-14.
    4. Bellgrau D, Modiano JF. The cytokine storm - An appropriate, over-reactive response to SARS-COV-2 or the wrong immune pathway? Scand J Immunol. 2020:e12979.
    5. Vanderhaeghen T, Vandewalle J, Libert C. Hypoxia-inducible factors in metabolic reprogramming during sepsis. FEBS J. 2020;287(8):1478-1495.
    CONFLICT OF INTEREST: None Reported
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    Aspirin?
    Giovanni Ghirga, Civitavecchia, Italy | Pediatrician
    Early treatment of COVID-19 is a very interesting topic.

    Hypercoagulability and thromboembolism are prominent features of severe COVID‐19, and ongoing anticoagulant use might be protective. Nevertheless, ongoing DOAC use was not associated with reduced risk of severe COVID‐19, indicating that prognosis would not be modified by early outpatient DOAC initiation (1). In nonhospitalized patients, routine prophylaxis for routine thromboembolism prevention is not recommended (2). Furthermore, remdesivir, hydroxychloroquine, lopinavir, and interferon regimens had little or no effect on hospitalized patients with Covid-19, as indicated by overall mortality, initiation of ventilation, and duration of hospital stay (3).

    At this
    writing, we have to admit that there is not effective treatment for early COVID-19. 

    However, we have an old drug with anti-inflammatory, antithrombotic, antiviral, antipyretic and analgesic properties that could be used early in patients affected by SARS-CoV-2 infection: acetyl salycilic acid (aspirin) (4).

    In adults at risk for moderate/severe COVID-19 and no contraindications, aspirin could be administered in anti-inflammatory doses used in autoimmune diseases, 3 gr/day in 4-6 doses, during the first week of disease and than continued at the antithrombotic dose of 81-325 mg/day for further 1-2 weeks. In the RECOVERY trial, aspirin is being tested at 150 mg/day (6). This dose has no anti-inflammatory effects and decreases the possibility that early aspirin administration could be beneficial to many aspects of COVID-19. A randomized trial with anti-inflammatory doses of aspirin is needed.

    References

    1. Benjamin Flam Viktor Wintzell Jonas F. Ludvigsson Johan Mårtensson Björn Pasternak. Direct oral anticoagulant use and risk of severe COVID‐19. Journal of Internal Medicine. First published: 01 December 2020. DOI:org/10.1111/joim.13205

    2. Gregory Piazza, David A. Morrow. Diagnosis, Management, and Pathophysiology of Arterial and Venous Thrombosis in COVID-19. JAMA. Published online November 23, 2020. doi:10.1001/jama.2020.23422.

    3. Harrington David P., Baden Lindsey R., Hogan Joseph W.. (2020) A Large, Simple Trial Leading to Complex Questions. N Engl J Med DOI:10.1056/NEJMe2034294.

    4. Chow Jonathan H, Khanna Ashish K, Kethireddy Shravan, Yamane David, Levine Andrea, et al. Aspirin Use is Associated with Decreased Mechanical Ventilation, ICU Admission, and In-Hospital Mortality in Hospitalized Patients with COVID-19, Anesthesia & Analgesia: October 21, 2020. DOI:10.1213/ANE.000000000000529

    5. Baron JA, Senn S, Voelker M, Lanas A, Laurora I, Thielemann W, Bruckner A and McCarthy D: Gastrointestinal adverse effects of short-term aspirin use: A meta-analysis of published randomized controlled trials. Drugs R D. 13:9–16. 2013.

    6. The RECOVERY Trial is registered at ISRCTN50189673. EU Clinical Trials Register: EudraCT 2020-001113-21
. Clinical Trials.gov: NCT04381936
    CONFLICT OF INTEREST: None Reported
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