COVID-19: Medication therapy

Investigational Therapies

Treatment for those infected with SARS-CoV-2 focuses on supportive care which includes symptomatic management, hand hygiene and social distancing. While many treatments are under investigation there is no proven efficacy of any drug for human as of April 8th 2020.[1].Medication management at this time is targeted towards those requiring inpatient admission.

  • Symptomatic management

Antivirals

Lopinavir/Ritonavir

  • Known in the U.S as Kaletra, this HIV medication has been widely used in China to treat COVID patients.[2].
  • An RCT with 199 confirmed COVID-19 positive patients concluded that there was no benefit to treating hospitalized patients with Lopinavir/Ritonavir versus supportive care.[3]
  • Dose: 400/100mg BID x 10 days. [4]

Remdesivir

  • Previously used to treat Ebola[5] this medication inhibits viral RNA polymerase and has shown some promisinng invitro activity against SARS-CoV-2.
  • A recent small study among 53 patients with severe symptoms from COVID-19 were given Remdesivir for compassionate use. 68% percent of patients showed some clinical improvement.[6]
  • A large NIH funded trial is currently underway to assess the efficacy of this medication [7]
  • Consider using in hospitalized patients with severe symptoms and significant Oxygen requirements
  • Contact Gilead directly for use: compassionateaccess@gilead.com
  • Dose: 200mg IV one time. Then 100mg IV once daily for 10 days. [8]

Oseltamivir

  • Coronaviruses do not utilize neuraminidase for the budding stage of reproduction and therefore no activity is expected.
  • Several small trials have not shown any benefit in patients with COVID-19. [9]

Baloxavir marboxil

  • Several clinical trials are underway however there is no evidence at this time for the efficacy of Baloxavir marboxil in treating COVID-19

Favipiravir

  • A small, open label, non-randomized trial in China has shown promising results and has not been peer reviewed.[10]
  • A small prospective, open label study conducted in China has shown promise in symptom reduction for moderatly ill patients with COVID-19 and has not yet been peer reviewed [11]

Ribavirin

  • Has been used in patients with MERS with inconclusive results.[12]
  • Small trials in China and North America have failed to establish a therapeutic benefit of Ribavirin. [13]

Chloroquine/Hydroxychloroquine

  • Antimalarial medication perhaps the most widely used in COVID-19 patients.
  • Limited in vitro data showing efficacy of Chloroquine against SARS-CoV-2.[14]
  • A systematic review of the efficacy of Chloroquine has shown promise in inhibiting replication of SARS-CoV-2 in vitro. [15]
  • A small French study with 20 patients showed benefit in reducing symptoms and viral carriage when combined with Azithromycin. [16]
  • Currently part of the treatment algorithim for COVID-19 inpatients in many hospitals.[17]
  • Despite the lack of evidence, the FDA has approved hydroxychloroquine use for the treatment of COVID-19. [18]
  • Dosage: *400mg PO BID x1day. Then 200mg BID x 4 days. (total 5 day course) [19]

Azithromycin

  • Macrolide antibiotic with purported anti-inflammatory effects in certain respiratory conditions such as COPD.
  • A small French study with 20 patients showed benefit in reducing symptoms and viral carriage when combined with Hydroxychloroquine. [20]
  • Recommended if there is concern for bacterial superinfection[21]
  • Dosage: 500mg x 1 day. Then 250mg x 4 days.

Immunomodulators

Interferon

  • Typically used in combination with ribavirin, interferons have been studied for patients with other coronaviruses, with mixed results. Their adverse effect profiles are also generally unfavorable.

Tocilizumab

  • FDA approved Interleukin-6 (IL-6) monoclonal antibody receptor antagonist used to treat rheumatoid arthritis and cytokine release storm syndrome.
  • Multiple anecdotal reports and cases showing marked improvement in oxygenation and clinical outcome after drug administration.[22] [23]
  • FDA approved randomized double-blinded clinical trial under way to evaluate its safety and efficacy. [24]
  • Dosage: Typically 8 mg/kg single dose, though some reports suggest giving repeated dosages in critically ill patients. [25]

Other experimental agents


Anticoagulation

  • Anticoagulation may be associated with lower mortality due to COVID-19 associated vascular thromboemboli resulting in increased dead space ventilation. [26]
  • Do not give anticoagulation to patients who have a high risk of bleeding as judged by the treating physician.
  • Before starting anticoagulation, check cbc, pt/ptt, d-dimer. Hold anticoagulation if platelet count <50,000 or INR >1.5.
  • In admitted patients with moderate or severe COVID-19:
  • High risk: No definitive criteria, but clinician should use a combination of respiratory distress, o2 requirement, elevated d-dimer, creatinine, and crp in making determination.

Dosing

  • ICU: Heparin drip per PE protocol (goal PTT 70 - 110) or Enoxaparin SC 1mg/kg BID.
  • High risk admitted patients:
    • CrCl > 50: Enoxaparin SC 1m/kg BID
    • CrCl <50:
      • On renal replacement Therapy: Apixaban 5mg PO BID or heparin drip PE protocol.
      • Not on renal replacement Therapy: Apixaban 5mg PO BID or Adjusted Dose Enoxaparin.
  • Not high risk:
    • Apixaban 2.5-5.0mg PO BID or Enoxaparin SC 40mg QD.

Glucocorticoids

    • Indicated in patients with asthma, COPD, and refractory septic shock with COVID-19.
    • The CDC and WHO recommend against routinely using corticosteroids in the initial treatment of COVID-19 patients without ARDS. [27]
    • In patients who have confirmed COVID-19 pneumonia and developed ARDS, there is a weak recommendation for starting steroids to blunt the cytokine storm. [28]
    • Dose: Methylprednisolone 1 to 2 mg/kg/day for 5 to 7 days.

Convalescent Plasma

  • Prior studies with convalescent plasma involving SARS, H1N1, and Ebola have had proven benefit in critically ill patients. [29]
  • Involves obtaining plasma/antibodies from patients who have recovered from COVID-19 and injecting them into critically ill patients.
  • Shown to have possible clinical improvement in patients with severe ARDS and COVID-19. [30]

Contraindicated Therapies

  • NSAIDS
    • There is anecdotal evidence to suggest that NSAIDs could potentially harm patients infected with COVID-19.[31]
    • Some experts suggest avoiding NSAIDs altogether while recommending the use of paracetamol/acetaminophen instead. [32]
  • ACEi/ARBs
    • There is an increase in mortality in patients with both hypertension and COVID-19 infection. [33]
    • ACEi and ARBs, used in the treatment of hypertension, has been postulated to contribute to the increased mortality by upregulating membrane-bound angiotensin-converting enzyme 2 (ACE2) which allows COVID-19 entry into human cells. [34]
    • Currently, however, there is insufficient evidence to recommend against using ACEi and ARBs in patients with COVID-19. [35]
  • Nebulizers
    • Avoid nebulizers as they are generally ineffective and may aerosolize virus
    • Albuterol with spacer is safer, though probably ineffective unless co-occuring reactive airway disease
      • MDI equivalents: Albuterol or ipratropium
        • <20 kg or 5yrs old: 4-5 puffs with a spacer every 20 minutes. 4 breaths between puffs.
        • >20 kg or 5yrs old: 8-10 puffs with a spacer every 20 minutes. 4 breaths between puffs.

See Also

References

  1. Auwaerter. Johns Hopkins Antibiotic guide. Coronavirus COVID-19. April 8 2020
  2. https://www.reuters.com/article/us-health-coronavirus-china-wuhan-hospit/key-china-coronavirus-hospital-says-hiv-drug-beneficial-to-patients-idUSKCN21R1LX
  3. Cao, B., Wang, Y., Wen, D., Liu, W., Wang, J., Fan, G., ... & Li, X. (2020). A trial of lopinavir–ritonavir in adults hospitalized with severe Covid-19. New England Journal of Medicine.
  4. https://www.massgeneral.org/assets/MGH/pdf/news/coronavirus/mass-general-COVID-19-treatment-guidance.pdf
  5. Auwaerter. Johns Hopkins Antibiotic guide. Coronavirus COVID-19. April 8 2020
  6. Grein, J., Ohmagari, N.,...Oda, R (2020). Compassionate Use of Remdesivir for Patients with Severe COVID-19. New England Journal of Medicine.
  7. https://clinicaltrials.gov/ct2/show/NCT04280705
  8. https://www.massgeneral.org/assets/MGH/pdf/news/coronavirus/mass-general-COVID-19-treatment-guidance.pdf
  9. Wang D, Hu B, Hu C, et al. Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel Coronavirus-Infected Pneumonia in Wuhan, China. JAMA. E-pub Date: aheadofprint February 2020. DOI # 10.1001/jama.2020.1585 . https://www.ncbi.nlm.nih.gov/pubmed/32031570
  10. https://www.jwatch.org/na51293/2020/04/09/favipiravir-potential-antiviral-covid-19
  11. https://www.medrxiv.org/content/10.1101/2020.03.17.20037432v3
  12. Arabi YM, et al. Ribavirin and Interferon Therapy for Critically Ill Patients With Middle East Respiratory Syndrome: A Multicenter Observational Study. Clin Infect Dis. 2019 Jun 25. https://www.ncbi.nlm.nih.gov/pubmed/31925415.
  13. Devaux CA1, Rolain JM2, Colson P2, Raoult D2. New insights on the antiviral effects of chloroquine against coronavirus: what to expect for COVID-19?. Int J Antimicrob Agents. 2020 Mar 12:105938. doi: 10.1016/j.ijantimicag.2020.105938.
  14. Gao J, Tian Z, Yang X. Breakthrough: Chloroquine phosphate has shown apparent efficacy in treatment of COVID-19 associated pneumonia in clinical studies. Biosci Trends. 2020. [PMID:32074550]
  15. Cortegiani A1, Ingoglia G2, Ippolito M2, Giarratano A2, Einav S3.A systematic review on the efficacy and safety of chloroquine for the treatment of COVID-19.J Crit Care. 2020 Mar 10. pii: S0883-9441(20)30390-7. doi: 10.1016/j.jcrc.2020.03.005.
  16. Gautret P, Lagier JC, Parola P, et al. Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial. Int J Antimicrob Agents. 2020:105949. [PMID: 32205204] doi:10.1016/j.ijantimicag.2020.105949
  17. https://www.massgeneral.org/assets/MGH/pdf/news/coronavirus/mass-general-COVID-19-treatment-guidance.pdf
  18. “Emergency Use Authorization.” US Food and Drug Administration. https://www.fda.gov/emergency-preparedness-and-response/mcm-legal-regulatory-and-policy-framework/emergency-use-authorization. Accessed 3/30/2020.
  19. https://www.massgeneral.org/assets/MGH/pdf/news/coronavirus/mass-general-COVID-19-treatment-guidance.pdf
  20. Gautret P, Lagier JC, Parola P, et al. Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial. Int J Antimicrob Agents. 2020:105949. [PMID: 32205204] doi:10.1016/j.ijantimicag.2020.105949
  21. https://www.massgeneral.org/assets/MGH/pdf/news/coronavirus/mass-general-COVID-19-treatment-guidance.pdf
  22. Xu X et al. Effective Treatment of Severe COVID-19 Patients with Tocilizumab. Unpublished study. 2020) https://www.ser.es/wp-content/uploads/2020/03/TCZ-and-COVID-19.pdf
  23. Sanders JM, Monogue ML, Jodlowski TZ, Cutrell JB. Pharmacologic Treatments for Coronavirus Disease 2019 (COVID-19): A Review. JAMA. Published online April 13, 2020. doi:10.1001/jama.2020.6019
  24. “Roche Initiates Phase III Clinical Trial of Actemra/RoActemra in Hospitalised Patients with Severe COVID-19 Pneumonia.” Roche, www.roche.com/media/releases/med-cor-2020-03-19.htm.
  25. Luo, Pan. “Tocilizumab Treatment in COVID-19: A Single Center Experience.” Journal of Medical Virology, 2020, doi:10.1002/jmv.25801.
  26. Tang et al. J Thromb Haemost 2020 Mar 27. PMID: 32220112
  27. Clinical Management of Severe Acute Respiratory Infection When COVID-19 Is Suspected.” World Health Organization, World Health Organization, www.who.int/publications-detail/clinical-management-of-severe-acute-respiratory-infection-when-novel-coronavirus-(ncov)-infection-is-suspected.
  28. Poston JT, Patel BK, Davis AM. Management of Critically Ill Adults With COVID-19. JAMA. Published online March 26, 2020. doi:10.1001/jama.2020.4914
  29. Chen, Long et al. “Convalescent plasma as a potential therapy for COVID-19.” The Lancet. Infectious diseases vol. 20,4 (2020): 398-400. doi:10.1016/S1473-3099(20)30141-9
  30. “Shen C, Wang Z, Zhao F, et al. Treatment of 5 Critically Ill Patients With COVID-19 With Convalescent Plasma. JAMA. Published online March 27, 2020. doi:10.1001/jama.2020.4783”
  31. Willsher, Kim. “Anti-Inflammatories May Aggravate Covid-19, France Advises.” The Guardian, Guardian News and Media, 14 Mar. 2020, www.theguardian.com/world/2020/mar/14/anti-inflammatory-drugs-may-aggravate-coronavirus-infection.
  32. Day, Michael. “Covid-19: Ibuprofen Should Not Be Used for Managing Symptoms, Say Doctors and Scientists.” Bmj, 2020, p. m1086., doi:10.1136/bmj.m1086.
  33. Wu C, Chen X, Cai Y, et al. Risk factors associated with acute respiratory distress syndrome and death in patients with coronavirus disease 2019 pneumonia in Wuhan, China. JAMA Intern Med. Published online March 13, 2020. doi:10.1001/jamainternmed.2020.0994
  34. Fang, Lei, et al. “Are Patients with Hypertension and Diabetes Mellitus at Increased Risk for COVID-19 Infection?” The Lancet Respiratory Medicine, vol. 8, no. 4, 2020, doi:10.1016/s2213-2600(20)30116-8.
  35. Patel AB, Verma A. COVID-19 and Angiotensin-Converting Enzyme Inhibitors and Angiotensin Receptor Blockers: What Is the Evidence? JAMA. Published online March 24, 2020. doi:10.1001/jama.2020.4812