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Effect of hydroxychloroquine with or without azithromycin on the mortality of COVID-19 patients: a systematic review and meta-analysis

Fiolet et al., Clinical Microbiology and Infection
Aug 2020  
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HCQ for COVID-19
1st treatment shown to reduce risk in March 2020
*, now with p < 0.00000000001 from 411 studies, recognized in 46 countries.
No treatment is 100% effective. Protocols combine treatments. * >10% efficacy, ≥3 studies.
4,300+ studies for 75 treatments.
Meta analysis of late stage studies (and one early treatment study with only 2 deaths), showing HCQ RR 0.83 [0.65-1.06], before exclusions RR 0.80 [0.65-1.0].
Authors claim "HCQ alone is not effective", but the result directly contradicts this, RR 0.83 [0.65-1.06], i.e., inconclusive but much more likely to be effective than not.
There are many errors in this meta analysis which introduce critical bias, for example:
- Very biased sample of studies, including <4% of early treatment studies (only 1), and <30% of late treatment studies, focused on negative studies.
- Arshad et al. (propensity matched HR 0.49, p=0.009) was excluded because the authors claim a "critical" risk of confounding bias due to steroid use, however steroids were controlled for in the multivariate and propensity analyses1.
- For Skipper et al., authors use an RR of 1.01, however the study had one hospitalized control death and one non-hospitalized HCQ death. Since the HCQ death was non-hospitalized, it may not be caused by COVID-19, or the patient did not receive standard care, therefore this should not be treated as equal to the control death. Further, medication adherence was only 77%, the HCQ patient may not have taken the medication (Skipper et al. neglects to answer this question). In any case, including a trial with only 1-2 deaths is likely to increase bias.
- Cavalcanti et al. received the lowest bias rating, despite having treatment delayed up to 14 days after symptoms, randomizing 14% of patients in the ICU, having significant protocol deviations, unusually low medication adherence, randomization that resulted in 64.3% male patients (HCQ) vs. 54.2% (control), and excluding patients already receiving longer and potentially therapeutic doses of the study treatments.
- Sbidian el al. received the lowest bias rating, however many more control patients are still in hospital at 28 days suggesting there will be a significant improvement when extending past 28 days.
- The RECOVERY trial received the lowest bias rating, despite using a very high dose likely responsible for the increased mortality. Results of this trial are not relevant to use at normal dosages.
- Inclusion criteria required RT-PCR confirmed cases, but this was disregarded when including Horby et al. (very negative, excessive dose) and Skipper et al.
- Authors do not consider different treatment delays, risk level of patients, differences in dosage, or usage of Zinc.
Also see many other reports of problems and fatal flaws:2-6
This analysis is also missing several recent studies, for a more up-to-date analysis see7.
8 meta analyses show significant improvements with hydroxychloroquine for mortality8-11, hospitalization8, recovery12, combined death/hospitalization/cases13, and cases14,15.
Currently there are 39 HCQ for COVID-19 early treatment studies, showing 76% lower mortality [61‑85%], 67% lower ventilation [-710‑99%], 31% lower ICU admission [1‑53%], and 41% lower hospitalization [28‑51%].
Fiolet et al., 26 Aug 2020, peer-reviewed, 6 authors.
This PaperHCQAll
Effect of hydroxychloroquine with or without azithromycin on the mortality of coronavirus disease 2019 (COVID-19) patients: a systematic review and meta-analysis
Thibault Fiolet, Anthony Guihur, Mathieu Edouard Rebeaud, Matthieu Mulot, Nathan Peiffer-Smadja, Yahya Mahamat-Saleh
Clinical Microbiology and Infection, doi:10.1016/j.cmi.2020.08.022
Background: Hydroxychloroquine or chloroquine with or without azithromycin have been widely promoted to treat coronavirus disease 2019 (COVID-19) following early in vitro antiviral effects against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Objective: The aim of this systematic review and meta-analysis was to assess whether chloroquine or hydroxychloroquine with or without azithromycin decreased COVID-19 mortality compared with the standard of care.
Transparency declaration All authors declare no support from any organization for the submitted work other than that described above; no financial relationships with any organizations that might have an interest in the submitted work in the previous 3 years; and no other relationships or activities that could appear to have influenced the submitted work. Authors' contributions TF designed the research. TF, MR, AG, MM, NPS and YMS conducted the research. TF performed the statistical analysis and wrote the first draft of the paper. MR, AG, MM, NPS and YMS contributed to the writing of the paper. All authors contributed to the data interpretation, revised each draft for important intellectual content, and read and approved the final manuscript. Appendix A. Supplementary data Supplementary data to this article can be found online at
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Late treatment
is less effective
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