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

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 (meta analysis)

Fiolet et al., Effect of hydroxychloroquine with or without azithromycin on the mortality of COVID-19 patients: a systematic.., Clinical Microbiology and Infection (meta analysis)

Aug 2020 Source PDF

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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 analyses [ijidonline.com].

- 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: [clinicalmicrobiologyandinfection.com, francesoir.fr, mediterranee-infection.com, twitter.com, twitter.com (B)]

This analysis is also missing several recent studies, for a more up-to-date analysis see [IHU Marseille].

Currently there are 36 HCQ early treatment studies and meta analysis shows:

Outcome	Improvement
Mortality	72% lower [57‑81%]
Ventilation	67% lower [-710‑99%]
ICU admission	28% lower [-17‑55%]
Hospitalization	41% lower [28‑52%]

Important missing comments or errors? Let us know.

Fiolet et al., 26 Aug 2020, peer-reviewed, 6 authors.

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Abstract: Clinical Microbiology and Infection 27 (2021) 19e27 Contents lists available at ScienceDirect Clinical Microbiology and Infection journal homepage: www.clinicalmicrobiologyandinfection.com Systematic review 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 1, 2, *, Anthony Guihur 3, Mathieu Edouard Rebeaud 3, Matthieu Mulot 4, Nathan Peiffer-Smadja 5, 6, 7, Yahya Mahamat-Saleh 1, 2 CESP (Centre for Research in Epidemiology and Population Health), Facult e de M edecinedUniversit e Paris-Sud, Facult e de M edecinedUVSQ, INSERM, Universit e Paris Saclay, Villejuif, France Gustave Roussy, Villejuif, France 3 Department of Plant Molecular Biology, Faculty of Biology and Medicine, University of Lausanne, Switzerland 4 ^tel, Switzerland Laboratory of Soil Biodiversity, Faculty of Science, University of Neucha 5 Universit e de Paris, IAME, INSERM, Paris, France 6 National Institute for Health Research Health Protection Research Unit in Healthcare Associated Infections and Antimicrobial Resistance, Imperial College, London, UK 7 Infectious and Tropical Diseases Department, Bichat-Claude Bernard Hospital, AP-HP, Paris, France 1 2 a r t i c l e i n f o a b s t r a c t Article history: Received 6 July 2020 Received in revised form 10 August 2020 Accepted 15 August 2020 Available online 26 August 2020 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. Data sources: PubMed, Web of Science, Embase Cochrane Library, Google Scholar and MedRxiv were searched up to 25 July 2020. Study eligibility criteria: We included published and unpublished studies comparing the mortality rate between patients treated with chloroquine or hydroxychloroquine with or without azithromycin and patients managed with standard of care. Participants: Patients 18 years old with conﬁrmed COVID-19. Interventions: Chloroquine or hydroxychloroquine with or without azithromycin. Methods: Effect sizes were pooled using a random-effects model. Multiple subgroup analyses were conducted to assess drug safety. Results: The initial search yielded 839 articles, of which 29 met our inclusion criteria. All studies except one were conducted on hospitalized patients and evaluated the effects of hydroxychloroquine with or without azithromycin. Among the 29 articles, three were randomized controlled trials, one was a nonrandomized trial and 25 were observational studies, including 11 with a critical risk of bias and 14 with a serious or moderate risk of bias. After excluding studies with critical risk of bias, the meta-analysis included 11 932 participants for the hydroxychloroquine group, 8081 for the hydroxychloroquine with azithromycin group and 12 930 for the control group. Hydroxychloroquine was not signiﬁcantly associated with mortality: pooled relative risk (RR) 0.83 (95% CI 0.65e1.06, n ¼ 17 studies) for all studies and RR ¼ 1.09 (95% CI 0.97e1.24, n ¼ 3 studies) for randomized controlled trials. Hydroxychloroquine with azithromycin..

Late treatment
is less effective

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