Treatment with HCQ was associated with lower mortality in patients admitted with COVID-19.
This study has strengths and limitations. Patients were not randomized and the differences in mortality may be explained by factors other than the use of HCQ. In an effort to control for the severity of disease, available markers were considered, and adjusted for, in all the models. The observation of a large number of unselected patients admitted in 17 hospitals, and the analyses run with some variations to test the consistency of the results are also strengths of this study. However, residual confounding is always present in all observational research. The association, that was consistent across a set of models that adjusted for different potential confounders, provides support to an independent positive effect of HCQ. For all models, the sensitivity analyses described in methods were used to assess the impact of missing data on the two markers of disease severity, and results were consistent with those presented.
HCQ has been used in all phases of COVID-19 since two studies, with no control arm and small sample size, published in March 2020, reported it to be associated with a reduction of the viral carriage and clinical improvement [9, 10, 21]. This has allowed for its effects to be observed since then in a large number of different patients in many countries. Our results, showing that HCQ is associated with positive outcomes, are consistent with the ones first reported in March 2020. A number of observational studies later conducted in China, France, Spain (in a hospital not included in our project), and the USA, have also reported the association between HCQ and lower mortality [22,23,24,25,26,27]. Three of these studies included over 2000 participants [23, 24, 26]. In one of these studies, only patients having mechanical ventilation were included . In another one, HCQ was also associated with lower probability of admission to intensive care, shorter hospital admissions, and shorter duration of viral shedding . In two of these studies, favourable results of HCQ combined with azithromycin were reported [23, 24], and in another one, the lower mortality was observed for those on HCQ in combination with azithromycin and zinc . The later study was based on primary care, and reported an association between treatment and lower rates of hospital admissions, as well. Another observational study conducted in primary care, were mortality was not the outcome, showed significantly shorter time to clinical recovery for those treated with HCQ or HCQ plus azithromycin . In our study, the addition of azithromycin to HCQ does not seem to add any clear benefit. A large multicentre observational study reported no association between HCQ, or HCQ with azithromycin, and lower mortality but significantly higher rates of discharge home were observed for patients treated by HCQ .
In a recent meta-analysis, studies were classified as big data, when electronic medical records had been used, or clinical studies, when details of treatments were reported and the study had been conducted by the same physicians who cared for the patients. It reported, among clinical studies, an association of chloroquine derivates with clinical improvement, lower mortality, and viral carriage . Finally, a small RCT reported the association of HCQ with shorter time both to clinical recovery and to reach viral RNA negativity .
The absence of any positive effects of the treatment with HCQ has also been reported. A number of observational studies have reported that HCQ, either alone or in combination with azithromycin, was not associated with lower mortality [32,33,34,35]. Three of these studies included over 1000 participants [32, 34, 35]. One of these studies included patients who needed oxygen  and another one used mortality or need for intubation as an outcome  Two RCTs have also reported no association between HCQ and survival [36, 37]. One of them also reported no benefit in need for admissions or clinical improvement . The lack of clinical improvement was reported in another trial . Finally, two more RCTs have reported no association between HCQ and virological clearance  or prevention of disease in individuals exposed to it . A number of factors could explain the difference between our results and the ones observed in these studies [32,33,34,35,36,37,38,39,40] including the following: the clinical–epidemiological design of our work;  the involvement of all patients admitted with COVID-19, regardless their past medical history, the time between onset of symptoms and the start of treatment, the duration of admission, and the need for oxygen; the different statistical approach; and the observation in our work of patients from private hospitals, who are likely to have a high socioeconomic status . The safety of the HCQ has been questioned, as it could negatively impact the immune response to the virus, or cause abnormalities in the ECG [33, 42, 43]. However, none of the studies that we have reviewed, reporting no benefit on HCQ, show an increased mortality associated with it [32,33,34,35,36,37,38,39,40].
Further RCTs, observational studies, and summaries of both types of evidence to assess the associations between HCQ and survival are necessary. Future studies could also address at what dosage, and in what phase of the disease, does HCQ lead to the best possible outcome, for patients with different past medical histories . The interventional evidence on the management of COVID-19 is still limited. Therefore, clinicians could acknowledge the results presented in this study. The positive effect of HCQ seems consistent and its use could be considered in clinical settings. HCQ is easy to administer, and its use in ambulatory patients, to reduce symptoms, prevent admissions, decrease mortality, and the transmission of the disease, could also be considered by clinicians and future researchers.