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Journal Club: Hydroxychloroquine & azithromycin for COVID-19

Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial

Discussed April 3, 2020

Please email Emily for a copy of her slides from Journal Club!

Key clinical take-aways from this article: 

• Why we should discuss it: first clinical trial data published on this treatment, 3/17/2020 - things are coming out in real time during the pandemic as options for treating patients around the world, but we need to look at the quality of these trials. This paper is super super flawed but worth looking at since it's making a splash. 

• Open-label non-randomized controlled trial with 36 patients diagnosed with SARS-CoV-2. Six of these patients were asymptomatic, 22 had upper respiratory tract infection symptoms and eight had lower respiratory tract infection symptoms. Twenty patients were assigned to the treatment group, and received HCQ 200mg three times a day for ten days. The control group received usual care. Six of the patients in the treatment group were also prescribed azithromycin to prevent bacterial superinfection.
• The main outcome of the trial was SARS-CoV-2 carriage at Day 6, tested using PCR of SARS-CoV-2 RNA from nasopharyngeal swabs.
• The results showed that patients in the treatment group were significantly more likely to test negative for the virus on Day 6 than patients in the control group (70% vs 12.5% virologically cured, p<0.001).
• All 6 patients who were treated with a combination of HCQ and azithromycin tested negative on Day 6.
• The authors argue that this finding speaks to the effectiveness of HCQ and a potential synergistic effect of its combined treatment with azithromycin.
  • There has since been a run on HCQ and a shortage for other patients (such as for lupus) - some are "thanked for their sacrifice" when their medications are stopped for "life-saving" treatment of COVID-19 patients instead. 
• SO MANY ISSUES, confounders, biases

Concerns and Limitations

• Not randomized to treatment and control groups - allocation bias
• 6 additional patients were recruited but lost to follow up
• Authors excluded these patients and did not use ITT (bias warning!)
• 48 patients would have been needed to achieve power of 85% - sample size was only 36, so the study was underpowered (causes exaggeration of effect sizes and false-positive results )
• recurrences of positive test results?
• Many other trials already underway to look at HCQ and azithromycin again

Citation

Gautret P, Lagier JC, Parola P, Hoang VT, Meddeb L, Mailhe M, Doudier B, Courjon J, Giordanengo V, Vieira VE, Dupont HT, Honoré S, Colson P, Chabrière E, La Scola B, Rolain JM, Brouqui P, Raoult D. Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial. Int J Antimicrob Agents. 2020 Mar 20:105949. doi: 10.1016/j.ijantimicag.2020.105949. [Epub ahead of print] PubMed PMID: 32205204; PubMed Central PMCID: PMC7102549.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7102549/