More evidence from France and China that hydroxychloroquine not successful in treating COVID-19

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The anti-inflammatory drug hydroxychloroquine does not significantly reduce admission to intensive care or death in patients hospitalised with pneumonia due to COVID-19, finds a study from France. And a randomised clinical trial from China also shows that hospitalised patients with mild to moderate persistent COVID-19 who received hydroxychloroquine did not clear the virus more quickly than those receiving standard care. Adverse events were higher in those who received hydroxychloroquine.

Taken together, the results do not support routine use of hydroxychloroquine for patients with COVID-19.

Hydroxychloroquine can reduce inflammation, pain, and swelling, and is widely used to treat rheumatic diseases. It is also used as an anti-malarial drug. Lab tests showed promising results, but accumulating trial and observational evidence has called into question whether there are any meaningful clinical benefits for patients with COVID-19.

Despite this, hydroxychloroquine has already been included in Chinese guidelines on how best to manage the disease, and the US Food and Drug Administration (FDA) issued an emergency use authorisation to allow the drug to be provided to certain hospitalised patients. The FDA has since warned against use outside clinical trials or hospital settings due to the risk of heart rhythm problems.

In the first study, researchers in France assessed the effectiveness and safety of hydroxychloroquine compared with standard care in adults admitted to hospital with pneumonia due to COVID-19 who needed oxygen.

Of 181 patients, 84 received hydroxychloroquine within 48 hours of admission and 97 did not (control group). They found no meaningful differences between the groups for transfer to intensive care, death within 7 days, or developing acute respiratory distress syndrome within 10 days. The researchers say that caution is needed in the interpretation of their results, but that their findings do not support the use of hydroxychloroquine in patients hospitalised with COVID-19 pneumonia.

In the second study, researchers in China assessed the effectiveness and safety of hydroxychloroquine compared with standard care in 150 adults hospitalised with mainly mild or moderate COVID-19.

Patients were randomly split into two groups. Half received hydroxychloroquine in addition to standard care and the others received standard care only (control group). By day 28, tests revealed similar rates of COVID-19 in the two groups but adverse events were more common in those who received hydroxychloroquine. Symptom alleviation and time to relief of symptoms also did not differ meaningfully between the two groups.

While further work is needed to confirm these results, the authors say that their findings do not support the use of hydroxychloroquine to treat patients with persistent mild to moderate COVID-19.

Abstract 1
Objective: To assess the effectiveness of hydroxychloroquine in patients admitted to hospital with coronavirus disease 2019 (covid-19) pneumonia who require oxygen.
Design: Comparative observational study using data collected from routine care.
Setting: Four French tertiary care centres providing care to patients with covid-19 pneumonia between 12 March and 31 March 2020.
Participants: 181 patients aged 18-80 years with documented severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pneumonia who required oxygen but not intensive care.
Interventions: Hydroxychloroquine at a dose of 600 mg/day within 48 hours of admission to hospital (treatment group) versus standard care without hydroxychloroquine (control group).

Main outcome measures: The primary outcome was survival without transfer to the intensive care unit at day 21. Secondary outcomes were overall survival, survival without acute respiratory distress syndrome, weaning from oxygen, and discharge from hospital to home or rehabilitation (all at day 21). Analyses were adjusted for confounding factors by inverse probability of treatment weighting.
Results: In the main analysis, 84 patients who received hydroxychloroquine within 48 hours of admission to hospital (treatment group) were compared with 89 patients who did not receive hydroxychloroquine (control group). Eight additional patients received hydroxychloroquine more than 48 hours after admission. In the weighted analyses, the survival rate without transfer to the intensive care unit at day 21 was 76% in the treatment group and 75% in the control group (weighted hazard ratio 0.9, 95% confidence interval 0.4 to 2.1). Overall survival at day 21 was 89% in the treatment group and 91% in the control group (1.2, 0.4 to 3.3). Survival without acute respiratory distress syndrome at day 21 was 69% in the treatment group compared with 74% in the control group (1.3, 0.7 to 2.6). At day 21, 82% of patients in the treatment group had been weaned from oxygen compared with 76% in the control group (weighted risk ratio 1.1, 95% confidence interval 0.9 to 1.3). Eight patients in the treatment group (10%) experienced electrocardiographic modifications that required discontinuation of treatment.
Conclusions: Hydroxychloroquine has received worldwide attention as a potential treatment for covid-19 because of positive results from small studies. However, the results of this study do not support its use in patients admitted to hospital with covid-19 who require oxygen.

Authors
Matthieu Mahévas, Viet-Thi Tran, Mathilde Roumier, Amélie Chabrol, Romain Paule, Constance Guillaud, Elena Fois, Raphael Lepeule, Tali-Anne Szwebel, François-Xavier Lescure, Frédéric Schlemmer, Marie Matignon, Mehdi Khellaf, Etienne Crickx, Benjamin Terrier, Caroline Morbieu, Paul Legendre, Julien Dang, Yoland Schoindre, Jean-Michel Pawlotsky, Marc Michel, Elodie Perrodeau, Nicolas Carlier, Nicolas Roche, Victoire de Lastours, Clément Ourghanlian, Solen Kerneis, Philippe Ménager, Luc Mouthon, Etienne Audureau, Philippe Ravaud, Bertrand Godeau, Sébastien Gallien, Nathalie Costedoat-Chalumeau

Abstract 2
Objective: To assess the efficacy and safety of hydroxychloroquine plus standard of care compared with standard of care alone in adults with coronavirus disease 2019 (covid-19).
Design: Multicentre, open label, randomised controlled trial.
Setting 16 government designated covid-19 treatment centres in China, 11 to 29 February 2020.
Participants: 150 patients admitted to hospital with laboratory confirmed covid-19 were included in the intention to treat analysis (75 patients assigned to hydroxychloroquine plus standard of care, 75 to standard of care alone).

Interventions: Hydroxychloroquine administrated at a loading dose of 1200 mg daily for three days followed by a maintenance dose of 800 mg daily (total treatment duration: two or three weeks for patients with mild to moderate or severe disease, respectively).
Main outcome measure: Negative conversion of severe acute respiratory syndrome coronavirus 2 by 28 days, analysed according to the intention to treat principle. Adverse events were analysed in the safety population in which hydroxychloroquine recipients were participants who received at least one dose of hydroxychloroquine and hydroxychloroquine non-recipients were those managed with standard of care alone.
Results: Of 150 patients, 148 had mild to moderate disease and two had severe disease. The mean duration from symptom onset to randomisation was 16.6 (SD 10.5; range 3-41) days. A total of 109 (73%) patients (56 standard of care; 53 standard of care plus hydroxychloroquine) had negative conversion well before 28 days, and the remaining 41 (27%) patients (19 standard of care; 22 standard of care plus hydroxychloroquine) were censored as they did not reach negative conversion of virus. The probability of negative conversion by 28 days in the standard of care plus hydroxychloroquine group was 85.4% (95% confidence interval 73.8% to 93.8%), similar to that in the standard of care group (81.3%, 71.2% to 89.6%). The difference between groups was 4.1% (95% confidence interval –10.3% to 18.5%). In the safety population, adverse events were recorded in 7/80 (9%) hydroxychloroquine non-recipients and in 21/70 (30%) hydroxychloroquine recipients. The most common adverse event in the hydroxychloroquine recipients was diarrhoea, reported in 7/70 (10%) patients. Two hydroxychloroquine recipients reported serious adverse events.
Conclusions: Administration of hydroxychloroquine did not result in a significantly higher probability of negative conversion than standard of care alone in patients admitted to hospital with mainly persistent mild to moderate covid-19. Adverse events were higher in hydroxychloroquine recipients than in non-recipients.

Authors
Wei Tang, Zhujun Cao, Mingfeng Han, Zhengyan Wang, Junwen Chen, Wenjin Sun, Yaojie Wu, Wei Xiao, Shengyong Liu, Erzhen Chen, Wei Chen, Xiongbiao Wang, Jiuyong Yang, Jun Lin, Qingxia Zhao, Youqin Yan, Zhibin Xie, Dan Li, Yaofeng Yang, Leshan Liu, Jieming Qu, Guang Ning, Guochao Shi, Qing Xie

BMJ material

BMJ abstract 1

BMJ abstract 2

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