The SARS-CoV-2 pandemic infected 200 million people and killed 4.2 million people by August 4, 2021, corresponding to an overall infection fatality rate (IFR) of 2% [1]. Health agencies in Western countries have focused on contagion control measures (lockdown), late-stage hospitalized patients, intensive care units, and vaccination, but for reasons that are yet to be clarified, early treatment has not been emphasized [2, 3, 4]. In eastern countries such as China, India, Iran, and Saudi Arabia, where early treatment and prevention with repurposed antivirals, particularly hydroxychloroquine (HCQ), has been widely implemented [5, 6, 7, 8], lower IFRs than Western countries, where early treatment with orally available molecules has been overlooked or even discouraged, have been reported [1]. In addition, countries using chloroquine or HCQ as a treatment from the start of the epidemic had a much slower dynamic in daily deaths [9]. The antiviral effect of chloroquine and its derivatives (HCQ) against SARS-CoV-2 was identified as early as February 2020 through in vitro studies in early Chinese publications [10, 11] and a preliminary trial in our center [12]. The synergistic in vitro antiviral effect of the combination of HCQ with azithromycin (AZ) was further reported [13]. In addition, HCQ has several anti-inflammatory and antithrombotic properties [14], which is of particular interest in the context of COVID-19-associated inflammation and coagulopathy.

Our previous observational study [15] reported a beneficial effect on thousands of cases, but in- and outpatients were not analyzed separately. The largest publicly available ambulatory studies included an Iranian study with 28,759 outpatients and a study in Saudi Arabia with 5541 outpatients, both evidencing a 4-fold reduced risk of death with HCQ [5, 6]. The importance of earliness of treatment has also been recently emphasized by a Chinese study reporting that HCQ, when administered in the first 5 days after symptom onset, improves prognosis and reduces viral shedding [7]. The effect of early ambulatory treatment with HCQ combined with AZ on COVID-19 mortality has not been reported in a large series. Here, we evaluated the age-specific mortality of unselected adult outpatients infected with SARS-CoV-2 managed early in a dedicated COVID-19 day hospital offering standardized treatment based on HCQ+AZ. We also assessed whether the use of HCQ+AZ was associated with improved IFR and lower rates of intensive care unit (ICU) admission and hospitalization in a conventional ward (HC) in this cohort. A meta-analysis of studies assessing early HCQ in COVID-19 outpatients was conducted to test consistency with available literature.

Here, we demonstrated the feasibility and efficacy of early outpatient management with a combination HCQ+AZ treatment to prevent COVID-19-related death. In our cohort, as in the largest published ambulatory series (Table 3, Ref. [5, 6, 25, 26, 27, 28, 29, 30]), treatment with HCQ was not associated with serious cardiac side effects but was associated with a significant IFR decrease of 75%. The present cohort is among the largest cohorts of COVID-19 patients treated in the outpatient setting, with the lowest mortality rates: the IFR was 0.15% (0.06% among those treated with HCQ+AZ) versus 0.7% and 1.1% (0.30% and 0.39% among HCQ-treated patients) in the Iranian (169/22,784 patients with positive PCR) and Saudi ambulatory cohorts (61/5541 patients), respectively (Table 3) [5, 6].

In our cohort, the IFR among patients of all ages treated with HCQ+AZ was 60 per 100,000, which is much lower than the natural infection rate, even when evaluated under the best conditions, as in Iceland, where it was estimated to be 300 per 100,000 [31]. The IFR was also estimated to be 89 per 100,000 in patients who were 70 years of age in Denmark [32]. For the same age range in our cohort, the IFR was 41 per 100,000 (4/9700) for all ambulatory patients and 25 per 100,000 for those treated with HCQ+AZ (2/7823) (see Table 1).

The cardiotoxicity of HCQ, previously considered irrelevant to oral administration and usual doses [33], has been exaggerated by studies with a potential conflict of interest, notably in the retracted article published in the Lancet [34]. White [33] showed that the concentrations needed to inhibit the hERG channel responsible for QT prolongation were 4 to 14 times higher than the concentrations observed in plasma at usual doses. In our center, we developed a smartwatch electrocardiogram and artificial intelligence for assessing the cardiac rhythm safety of HCQ+AZ and did not find any QTc prolongation [35]. In the literature, ambulatory and not critically ill patients with COVID-19 treated with hydroxychloroquine, azithromycin and/or antiretrovirals develop a significant, but not relevant, QT interval prolongation [36]. As shown in our cohort, a simple clinical and biological evaluation with blood potassium assessment and the use of a first electrocardiogram allowed us to initiate treatment with acceptable safety in terms of potential arrhythmias.

The Fig. 4 show, in a meta-analysis, that all the studies carried out on outpatients, with minimal quality criteria (biological diagnosis, representative population with adequate control and at least 1 death), are all in the same direction (Table 3, Supplementary Tables 8,9, Supplementary Fig. 2). All these studies reported a similar magnitude (3-fold decrease in the risk of death), and showed that early treatment with hydroxychloroquine improve survival in COVID-19 outpatients in the community (n = 32,124 patients in 5 countries, Odds ratio 0.31 [0.20–0.47]) without heterogeneity (I${}^2$ = 0%). This is also confirmed in the non-hospital setting in nursing homes (Table 3, Supplementary Table 8). Almost all RCTs were excluded because of lack of systematic biological diagnosis or absence of death (Supplementary Table 9). Only 1 randomized controlled trial with PCR-proven diagnosis and at least 1 death was identified in the outpatient setting, probably because the sample size needed to identify a significant difference with sufficient power in mortality risk is difficult to achieve with such a design in this context. This RCT [27] reported a non-significant but beneficial effect of HCQ (Table 3). However, new RCTs with medical quality criteria are not expected to change results since it has been shown that results from RCT and observational studies did not differ significantly [37, 38]. Interestingly, early administration of fluvoxamine was found to prevent clinical deterioration, notably in outpatients [29, 39]. Strikingly, both fluvoxamine and HCQ interfere with the interaction between the viral protein nsp6 and the host sigma-1 receptor, previously identified as a key functional host-dependency factor [40, 41].

Fig. 4.

Meta-analysis on studies in the community evaluating HCQ as an ambulatory treatment to prevent COVID-19 mortality (n = 32,124). The Meta-analysis was performed using random effects modeling for odds ratios (OR). Chi square based Q test and I${}^2$ statistic were used to evaluate the statistical heterogeneity between the studies. Meta-analysis was performed with using the R package meta.

The major limitation of the present cohort is its lack of assessment of comorbidities. Patients not receiving HCQ tend to be older and have more comorbidities [28], and although we were able to control for age and sex, the present study was not adjusted for other key comorbidities and may be biased accordingly. However, consistency with 3 similar studies assessing the death outcome and controlling for comorbidities [5, 6, 25] was demonstrated by meta-analysis. In another study by Szente-Fonseca et al. [28], a beneficial effect of hydroxychloroquine, alone or in combination with prednisone, was found for hospitalization and death, but adjusted model was provided only for the hospitalization outcome. Taken together, these results suggest that early treatment with HCQ was consistently reported to prevent progression of COVID-19 in ambulatory patients, independently of age, gender, and comorbidities.

All outpatients reported here were considered non-severe by the day-hospital physician based on routine assessment of saturation and dyspnea, but data on accurate initial clinical assessment was not collected. Follow-up was not systematically proposed after May 2020, so hospitalizations in and transfers to critical care units outside our city hospitals (APHM) may have been overlooked. However, deaths were identified through the French national register, thereby controlling this bias. The strengths of our study include the large sample size, the homogeneous management of patients associated with the monocentric design, and the double collection of death data by means of two registers: a local (city public hospital system) and national (French National Register of Deceased Persons) register.

The evolving concept and success of sequenced multidrug therapy including either HCQ, fluvoxamin or ivermectin for outpatient COVID-19 in reducing hospitalization and death by ~85% was reported by several authors without any link of interest with our team which strengths the external validity of the present study (Table 3, Fig. 4) [2, 3, 4, 42]. In another non-hospital context, the efficacy of HCQ in nursing homes (Supplementary Table 8) [43, 44, 45] strengthen the external validity and further highlight the role of HCQ in the non-hospital setting.

Finally, there are old and nontoxic drugs with in vitro and preliminary clinical efficacy on SARS-CoV-2 infection, such as HCQ, zinc, ivermectin, or fluvoxamine [2, 3, 4, 21, 39, 46]. Early oxygen, immunomodulation and antithrombotic therapy may also prevent disease worsening [3, 47]. Such drugs may be neglected when political factors, massive funding and fear lead to irrational decisions [48], such as therapeutic nihilism [2]. It seems urgent that governments and health authorities take in hand the evaluation of nonprofitable drugs, which are probably more effective than the drugs developed for this pandemic. This requires a profound paradigm shift, the extent of which was revealed by COVID-19 and which would be in line with the reflections on Tamiflu, recently documented in the British Medical Journal [48]. As long as the planned obsolescence of drugs continues and remains the current standard in Western countries, these richest countries and, theoretically, the most scientifically advanced, will remain those with the highest COVID-19 fatality rate in the world.

HCQ, hydroxychloroquine; AZ, azithromycin; IFR, infection fatality rate.

MMillion designed and supervised the study, conducted the investigation, formal analysis and wrote the first draft of the manuscript, JCL participated in the study design, investigation and critical review, all authors (HTD, IR, CD, CT, NC, SA, CA, KB, BD, SE, MH, MMailhe, CP, PS, CT, SG, EJ, AGG, HC, LCJ, PC, PG, PEF, BM, JCD, PH, JYG, AJ, SH, KGL, YO, PP, PB) participated in the investigation and provided constructive criticism and comments, LD, CB and SC conducted the formal analysis and meta-analysis, DR designed and supervised the study, and final proofreading with key finalization of the text.

Data presented herein were collected retrospectively from the routine care setting using the electronic health recording system of the hospital. The retrospective nature of the study was approved by our institutional review board committee (Méditerranée Infection N${}^{\circ }$: 2021–007). As previously reported [15], for all patients, the prescription of HCQ+AZ was made during day hospital attendance by one of the physicians, after a collegial decision based on the most recent scientific data available and after assessment of the benefit/harm ratio of the treatment. According to European General Data Protection Regulation No 2016/679, patients were informed of the potential use of their medical data and that they could refuse the use of their data. Data processing was carried out in accordance with the reference methodology MR-004 registered on N${}^{\circ }$ MR 2020-151 in the AP-HM register and public register (https://www.health-data-hub.fr/projets).

This manuscript has been edited by a native English speaker. We thank the reviewers who helped in substantially improving and clarifying the manuscript with their many comments and suggestions. We are thankful to Sylvie Arlotto, Marion Bechet, Yacine Belkhir, Pierre Dudouet, Véronique Filosa, Marie-Thérèse Jimeno, Alexandra Kotovtchikhine, Line Meddeb, Cléa Melenotte, Malika Mokhtari, and Pierre Pinzelli. All medical students from Aix Marseille University; all nurses; all laboratory staff; all administrative, technical and security staff from Assistance Publique-Hôpitaux de Marseille and IHU Méditerranée Infection; all volunteer medical doctors; and the Bataillon des Marins Pompiers de Marseille for their help. Other medical volunteers who contributed to taking care of COVID-19 patients in 2020 are acknowledged at the end of the Supplementary data.

This work was funded by ANR-15-CE36-0004-01 and by ANR “Investissements d’avenir”, Méditerranée infection 10-IAHU-03 and was also supported by Région Provence-Alpes-Côte d’Azur. This work received financial support from the Mediterranean Infection Foundation.

The authors declare no conflict of interest. The funders/sponsors had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; or decision to submit the manuscript for publication. Funding sources had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the manuscript. Our group used widely available generic drugs distributed by many pharmaceutical companies.