Issue 4: Current treatment considerations (MARCH 27, 2020)

CURRENT TREATMENT CONSIDERATIONS

Chloroquine/ hydroxychloroqione (CQ/HCQ)1-11

  • CQ has been used worldwide for more than 70 years for malaria treatment and Chemoprophylaxis.
  • HCQ belongs to the same molecular family than CQ  and is also used for treatment of rheumatoid arthritis and systemic lupus erythematosus.
  • Both drugs have in vitro activity against SARS-CoV, SARS-CoV-2, and other coronaviruses. The mode of action may be through prevention of endocytotic-mediated uptake of SARS-CoV2.
  • HCQ may be more potent against SARS-CoV-2 than CQ and could serve as a better therapeutic approach than CQ for the treatment of SARS-CoV-2 infection due to a better safety profile.
  • Primary safety concern is cardiotoxicity with prolonged QT syndrome and hepatic/renal dysfunction in those with extended use.
  • Addition potential complications include:  chronic cardicardiotoxicity, cardiomyopathy, myopathy, blood and lymphatic system disorders (e.g. anemia), and irreversible retinal damage.
  • After oral administration HCQ is rapidly absorbed and has an average bioavailability of about 74 %.
  • HCQ is partially degraded to active metabolites and is excreted mainly via the kidneys but also via bile. Elimination is slow, the terminal elimination half-life is about 50 days (whole blood) or 32 days (plasma).
  • HCQ and CQ are renally excreted at about 40-50%.
  • Considering that the use of HCQ is particularly important in patients with systemic lupus erythematosus and kidney involvement.
  • HCQ dosing regimens for hemodialysis patients of 200 mg after dialysis sessions (3x/week) have been suggested.
  • Dose adjustment of HCQ should only be made at a GFR of <30mL/min with a maximum dose of 3mg/kg. This would be a dosage of 200mg HCQ per day for a 63 kg patient.
Figure 1. Potential mechanism by which chloroquine exerts therapeutic effects against COVID-19, involving suppression of PICALM, which prevents endocytosis-mediated uptake of SARS-CoV-2.11

 

Azithromycin12

A recent study by  Gautret and colleagues added the antibiotic azithromycin to the treatment regiment with HCQ.

  • This agent was given only to the patients that displayed with respiratory symptoms.
  • Azithromycin displays unusual antiviral properties, particularly noticeable in airway epithelial cells.
  • The combined effect of HCQ and azithromycin was hypothesized to reduce respiratory and systemic viral load and allow for faster recovery from the infection.
  • Caution should however be exercised with this combination for the potential development of severe QT prolongation.

REFERENCES:

  1. Zhou et al. JAntimicrob Chemother: 2020.
  2. Colson P et al., Int J Antimicrob Agents: 55, 105923, 2020.
  3. Stahlmann, and Lode,  2020.
  4. Cortegiani  et al.,J. Crit Care 2020.
  5. Wang et al. Cell Res: 30, 269-271, 2020.
  6. https://www.cdc.gov/coronavirus/types.html Accessed March 27, 2020.
  7. Liu et al.  Cell Discovery 6:16, 2020.
  8. Hydroxychloroquin-Ratiopharm, Fachinformation, 2019, Plaquenil, Package insert, 2018.
  9. Fiehn et al. 2020.
  10. Brescia Renal COVID task force.
  11. Hu et al. Nature Nanotechnology, 2020.
  12. Gautret et al. J. Antimicrob Agents, 2020.