Hydroxychloroquine and azithromycin for preventing complications

Clinical Question

Can chloroquine combined with azithromycin be used to prevent complications when administered in the initial stage of COVID-19 (note specific question, see prior articles for more complete discussion of medications).

Key Findings

  • There is insufficient data to support use of hydroxychloroquine (HCQ) and azithromycin to prevent complications of COVID-19.
  • Multiple organizations have now stopped clinical trials due to lack of support of efficacy as well as concern for risks, including the NIH and WHO. The FDA additionally revoked the emergency use authorization of HCQ.
  • The QT prolonging effect of chloroquine/hydroxychloroquine can be aggregated by azithromycin, increasing the concern for severe cardiac toxicity.
  • Chloroquine/hydroxychloroquine combined with azithromycin should not be prescribed to patients without close monitoring and individualized clinical evaluation.
  • It is challenging to evaluate the effectiveness of chloroquine and azithromycin in preventing COVID-19 complications due to multiple confounders in non-controlled environments. Multiple factors including age, presence of comorbidities, tobacco use, or immunocompromising conditions can all affect how patients respond to COVID-19.

Summary of Information

Chloroquine has shown antiviral activity against both DNA and RNA viruses, although this property has only been described through in vitro studies.[1] So far, the potential benefits of chloroquine have been suggested to result from the endolysosomal pathway and reported in non-clinical trials. However, there are proposed mechanisms to indicate that chloroquine may disrupt early stage of SARS-CoV-2 replication.[2] Nevertheless, these mechanisms are not clinically proven as there has yet to be a randomized, double-blind, controlled studies in COVID-19 patients.[3]

In May 2020, there was a retrospective analysis of hydroxychloroquine and azithromycin in 1,061 COVID-19 patients as an early treatment.[4] In this study, 91.7% of patients had a good clinical outcome, which was defined as the absence of viral shedding persistence at day 10 nor death or transfer to ICU. According to the safety data, 97.6% of patients experienced no adverse events and 2.3% of patients reported mild adverse events. The analysis concluded that this combination is both effective in controlling the infection and safe.

However, as with other retrospective studies, it is challenging to control for confounders. It is unknown whether the clinical outcome was resultant from the absence of immunocompromised conditions or comorbidities or the combination of hydroxychloroquine and azithromycin. Furthermore, there is an ongoing concern for safety. In the study, patients were monitored regularly, which would not be feasible in outpatient or lower-resourced inpatient settings. Although both hydroxychloroquine/chloroquine and azithromycin have been on the market for an extensive period of time with drug safety data, the true efficacy and safety when used in combination in COVID-19 patients remains under question.

And in June 2020, multiple organizations began withdrawing their support of HCQ given the lack of data supporting its use. The U.S. National Institute of Health (NIH) stopped recruiting into HCQ trials[5]; the U.K.-based Recovery trial stopped the HCQ arm of the study based on “no evidence of benefit” [6], the WHO dropped HCQ from its Solidarity trial,[7] and the FDA revoked the emergency use authorization.[8]

Gaps in Knowledge

Besides the need for clinical studies that specifically investigate the role of chloroquine and azithromycin in preventing COVID-19 complications, there is also a need to evaluate risk stratification to allow the appropriate administration of this drug combination to patients who can benefit the most from this therapy.

Author Information

Authors: Jon Zhou, Pharm.D., MPH
Completed on: June 17, 2020
Last revised on: Not yet revised

Reviewed by: Sara Baird MD
Reviewed on: June 20, 2020

This summary was written as part of the CoRESPOND Earth 2.0 COVID-19 Rapid Response at UC San Diego. For more information about the project, please visit http://earth2-covid.ucsd.edu

References

  1. Wang M, Cao R, Zhang L, et al. Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro. Cell Res. 2020;30(3):269-271.  [PMID:32020029]
  2. Savarino A, Boelaert JR, Cassone A, et al. Effects of chloroquine on viral infections: an old drug against today's diseases? Lancet Infect Dis. 2003;3(11):722-7.  [PMID:14592603]
  3. Principi N, Esposito S. Chloroquine or hydroxychloroquine for prophylaxis of COVID-19. Lancet Infect Dis. 2020.  [PMID:32311322]
  4. Million M, Lagier JC, Gautret P, et al. Early treatment of COVID-19 patients with hydroxychloroquine and azithromycin: A retrospective analysis of 1061 cases in Marseille, France. Travel Med Infect Dis. 2020.  [PMID:32387409]
  5. NIH halts clinical trial of hydroxychloroquine. National Institutes of Health (NIH). https://www.nih.gov/news-events/news-releases/nih-halts-clinical-trial-hydroxychloroquine. Published June 20, 2020. Accessed June 30, 2020.
  6. No clinical benefit from use of hydroxychloroquine in hospitalised patients with COVID-19. Recovery Randomised Evaluation of COVID-19 Therapy. https://www.recoverytrial.net/news/statement-from-the-chief-investigators-.... Published June 5, 2020.
  7. Q&A : Hydroxychloroquine and COVID-19. WHO. https://www.who.int/news-room/q-a-detail/q-a-hydroxychloroquine-and-covid-.... Accessed June 30, 2020.
  8. Coronavirus (COVID-19) Update: FDA Revokes Emergency Use Authorization for Chloroquine and Hydroxychloroquine. FDA. https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-u.... Published June 16, 2020. Accessed June 30, 2020.