Antimalarials and macrolides: a review of off-label pharmacotherapies during the first wave of the SARS-CoV-2 pandemic

Abstract We critically analyzed clinical trials performed with chloroquine (CQ) and hydroxychloroquine (HCQ) with or without macrolides during the first wave of COVID-19 and discussed the design and limitations of peer-reviewed studies from January to July 2020. Seventeen studies were eligible for the discussion. CQ and HCQ did not demonstrate clinical advantages that justified their inclusion in therapeutic regimens of free prescription for treatment or prophylactic purposes, as suggested by health authorities, including in Brazil, during the first wave. Around August 2020, robust data had already indicated that pharmacological effects of CQ, HCQ and macrolides as anti-SARS-CoV-2 molecules were limited to in vitro conditions and largely based on retrospective trials with low quality and weak internal validity, which made evidence superficial for decision-making. Up to that point, most randomized and nonrandomized clinical trials did not reveal beneficial effects of CQ or HCQ with or without macrolides to reduce lethality, rate of intubation, days of hospitalization, respiratory support/mechanical ventilation requirements, duration, type and number of symptoms, and death and were unsuccessful in increasing virus elimination and/or days alive in hospitalized or ambulatory patients with COVID-19. In addition, many studies have demonstrated that side effects are more common in CQ-or HCQ-treated patients.

The possible off-label use and pharmacological repositioning of CQ and HCQ have emphasized the multiple clinical arms of old drugs for new purposes (Ferreira et al., 2021).In this review, we critically analyzed the clinical trials carried out with CQ and HCQ with or without macrolides during the first wave of the COVID-19 pandemic, considering their design and limitations.

MATERIAL AND METHODS
To carry out a comprehensive and consistent analysis of prospective or retrospective, single-or multicenter, observational or analytical clinical trials already published in peer reviewed journals, only original qualitative, quantitative or mixed articles written in English were used in this review.The descriptors were chosen as Medical Subject Headings (MeSH) terms as follows: "clinical trial, COVID-19, chloroquine" or "clinical trial, COVID-19, hydroxychloroquine" and used for bibliographic searches in PubMed, ScienceDirect, Scopus and Scielo databases by three researchers (P.M.P.F., R.W.R.S., and D.P.B.) independently.Afterwards, data were compared and contrasted.Only studies available between January and July 2020 and mentioning these descriptors in the abstract or in the title were initially included.Duplicated and nonrelated articles, as well as in vitro studies, opinions, comments, letters to the editor, and reviews, were not considered for review.Within the PICO strategy [(P, current population; I, therapeutic, diagnostic or prognostic intervention; C, comparison; O, outcomes (results)], our FIGURE 1 -Proposed mechanisms for the antiviral actions of chloroquine and hydroxychloroquine against severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) and other viruses.Some antiviral mechanisms that have been recently proposed present general parallelisms and depend on the specific inhibition of autophagy steps, a well-known property of chloroquine, hydroxychloroquine and analogs.SARS-CoV-2 enters cells by binding the S protein to the angiotensin-converting enzyme 2 (ACE2) receptor on the cell target surface, which is triggered by the transmembrane protease serine 2 (TMPRSS2).The virus exposes its RNA, and through transcription and replication, the complex forms RNA strands that will be translated for the structural proteins.Structural proteins and RNA in the cytoplasm assemble into new viral particles, which are released by exocytosis to infect other cells.Chloroquine/hydroxychloroquine has shown an in vitro ability to block/delay these steps of infection.The transportation of both drugs is completely via passive diffusion (i.e., no transporters are involved).However, it remains unclear how changes in the endosomal environment, particularly changes in pH, may affect the integrity of the SARS-CoV-2 viral genome.To date, no medication has been shown to prevent SARS-CoV-2 transmission or treat COVID-19 specifically.
hypothesis was that chloroquine and hydroxychloroquine are effective against SARS-CoV-2 in humans.
As an eligibility criterion and considering evidence-based practice to carry out a critical analysis, we observed the data, rigor, credibility, and study design.In addition, the method of patient selection, the relationships between researchers and patients, ethical criteria, statistical analysis, confounding factors, data presentation, and limitations were also examined (Singh, 2013).Since macrolides (mainly azithromycin or less often clarithromycin) were part of most reports as well as government documents, they were included in the discussion but not in the bibliographic investigations.
All studies were conducted according to the Brazilianrules (Law 466/2012, National Health Council) and international guidelines (World Medical Association, Declaration of Helsinki, and Universal Declaration on Bioethics and Human Rights/UNESCO).

RESULTS
Most ar ticles published until July 2020 corresponded to in vitro studies, opinions, comments, letters to the editor, and reviews (or duplicated ones).The PRISMA diagram with details of the selection is shown in Figure 2.After exclusions, 17 clinical studies focusing on CQ or HCQ (with or without macrolides) were considered for the discussion.Each study was briefly described in Table I and sequentially commented throughout the text.600 mg of HCQ daily for 10 days plus 500 mg azithromycin on day 1, followed by 250 mg/ day for the next 4 days.
At the beginning of treatment, 10 of 11 patients had a fever and received nasal oxygen therapy.
No evidence of benefit of HCQ or CQ when used either alone or with a macrolide and these regimens were associated with increased risk of ventricular arrhythmias and death, which suggest these therapies should not be used outside of clinical trials.Additional post hoc analyses showed that self-reported use of zinc or vitamin C in addition to HCQ did not improve symptoms over use of HCQ alone.
HCQ failed to decrease prevalence or severity of symptoms over the 14day study period.
The incidence of hospitalization or death did not differ between treated and placebo groups.

DISCUSSION
In the beginning of the SARS-CoV-2 pandemic, studies with African green monkey kidney Vero E6 cells infected with strains of the new coronavirus-2019 revealed antiviral activity and EC 50 values of 23.9 and 5.47 μM and 6.14 and 0.72 μM in 24 and 48 h for CQ phosphate and HCQ sulfate, respectively (Wang et al., 2020).Similar studies indicated that the 50% maximal effective concentration for CQ (2.71, 3.81, 7.14, and 7.36 μM) was lower than that for HCQ (4.51, 4.06, 17.31, and 12.96 μM) (Liu et al., 2020).Some years before, the IC 50 of CQ for in vitro inhibition of SARS-CoV-1 in infected Vero E6 cells indicated approximation of plasma concentrations of CQ reached during treatment of acute malaria (Keyaerts et al., 2004) since 6 -6.5 mg/kg per day of HCQ sulfate could generate serum levels of 1.4 -1.5 μM in humans (Laaksonen, Koskiahde, Juva, 1974).
Based on PBPK model results, a loading dose of 400 mg twice daily of oral HCQ sulfate followed by a maintenance dose of 200 mg given twice daily for 4 days was recommended for SARS-CoV-2 infection, since it reached 3-fold the potency of CQ phosphate when administered at the same dosages in patients with rheumatoid arthritis (500 mg/dose).Similarly, the computationally simulated chloroquine concentration in lung tissue was higher than that in plasma, where the lung to plasma ratio increased with time and reached a ratio of approximately 400 (Yao et al., 2020).
In this context, it is important to emphasize that in addition to being deficient in angiotensin-converting enzyme 2 (ACE2) and transmembrane protease serine 2 (TMPRSS2), intrinsic nonspecific endocytic viral uptake mechanisms are responsible for viral entry in the Vero E6 line and a variety of other cell types (Murgolo et al., 2021).Indeed, chloroquine does block infection with SARS-CoV-2 in Calu-3 metastatic lung adenocarcinoma cells lacking ACE2 but expressing human TMPRSS2, and engineered expression of TMPRSS2 renders SARS-CoV-2 infection of Vero cells insensitive to CQ (Hoffmann et al., 2020a).These findings clearly indicate that CQ or HCQ will not exert antiviral activity in human lung tissue and will not be effective against COVID-19 (Hoffmann et al., 2002a), especially whether we take into consideration that the spike protein of SARS-CoV-2, which mediates viral entry, is activated by the endosomal-pH-dependent cysteine protease cathepsin L in some tissues but is pHindependent via TMPRSS2 in airway epithelial cells There were no differences among the groups in the proportional odds of having a higher (worse) score on the seven-point ordinal scale at 15 days and need for mechanical ventilation requirements (HCQ + azithromycin: 11 %; HCQ: 7.5 %; control: 6.9 %).
Adverse events were more common in patients who received HCQ + azithromycin (39.3 %) or HCQ alone (33.7 %), as well as prolongation of the QTc interval in HCQ with or without azithromycin.Elevation in liver enzymes was higher in patients receiving HCQ + azithromycin.
Thromboembolic or acute kidney injury events, days alive and free from respiratory support were similar among groups within 15 days.
This 7-day course of HCQ either with azithromycin did not result in better clinical outcomes but these regimens were more associated with the occurrence of hepatic damages and more frequent events of QTc interval prolongation.(Hoffmann et al., 2020b).Calu-3 cells, as the airway epithelium, present low amounts of cysteine protease cathepsin L (Park et al., 2016), and SARS-CoV-2 entry mainly occurs by TMPRSS2 (Hoffmann et al., 2020b).
Then, CQ and HCQ may block spike protein-driven entry, but this inhibition is a cell-specific pharmacodynamic response not observed in TMPRSS2 + pulmonary cells.
These effects indicate that some preclinical findings do not offer plausible reasons for clinical purposes before further mechanistic definitions.
All in vitro and computational analyses suggested doses and treatment schedules without tests on laboratory animals or humans, did not consider in vivo pharmacokinetic analyses, and claimed clinical recommendations and broad-spectrum conclusions about systemic anti-inflammatory actions of HCQ.Nonetheless, these early data encouraged researchers to carry out clinical trials with CQ and HCQ as supposable options to treat infected patients or prevent COVID-19.
The first clinical trial published after starting the COVID-19 pandemic was carried out in France.Gautret et al. (2020a) reported that HCQ (hydroxychloroquine sulfate) 600 mg/day for 10 days or HCQ plus azithromycin was effective in eliminating viral nasopharyngeal load as determined by reverse transcription polymerase chain reaction (RT-PCR), after 3-6 days in patients with COVID-19.It was an open, single and nonrandomized clinical trial, with a small sample (36 patients), higher average age in the treated group (51.2 years vs. 37.3 years), and omission of 6 (23%) patients excluded due to clinical worsening or loss of follow-up.No standardization of treatment according to the disease's severity was carried out, untreated patients enrolled involved another health center (it was not a control group), and all patients received the same type of treatment, regardless of the clinical condition, leading to worthless conclusions about the effectiveness of these drugs.In addition, this study did not provide details about comorbidities.
Shortly afterwards, another French open, prospective, and uncontrolled clinical trial considering identical dosages from Gautret et al. (2020a) showed conflicting results.Once again, a small group of 11 patients, without control or placebo.With a mean age (58.7 years) greater than the previous study, study, it was closer to the average age for most moderate and severe cases of COVID-19.They demonstrated that 2/3 (72.7%) of the patients presented a direct relationship between comorbidities and the severity of the disease (Molina et al., 2020).However, details about the use of supportive pharmacological therapies were not accessible.As in the previous study, there was no standardization of treatment according to COVID-19 severity, which excluded real correlations about progression of the pathology and the effectiveness of the treatment.
The first Brazilian clinical investigation called the CloroCovid-19 trial was carried out in Manaus, the largest city in the Amazon region.It enrolled 81 randomized patients who received high doses of CQ base (600 mg, twice per day for 10 days, total of 19 g CQ diphosphate or 12 g base) or lower doses (450 mg with or without placebo, divided into 10 days, total of 4.3 g CQ diphosphate or 2.7 g base).Among the 27 patients (paired sample analysis in both arms of the study), respiratory secretion on day 4 revealed negative conversion for only 6 patients (22%), and benefit for CQ-treated patients was not observed regarding lethality (Borba et al., 2020).This clinical trial was double-blind, analytical, without placebo/control group, parallel, and performed in a public hospital, representing the most common COVID-19 cases in Brazil.This indicates that a higher dosage of CQ is not medically aplicable for the treatment of severe COVID-19, especially among patients also receiving azithromycin and oseltamivir, because of safety concerns regarding QTc interval prolongation and increased lethality.Patients not excluded from the studies based on the QTc interval may represent the Brazilian reality, since most patients treated with CQ/HCQ with or without azithromycin are not submitted to cardiological followups (e.g., ECG monitoring) before starting the treatment.The lack of lung radiological/tomographic examinations during the trial limited the monitoring of the clinical respiratory conditions (improvement or worsening).The fact that all patients received ceftriaxone, azithromycin or oseltamivir may have influenced the appearance of side effects and hampered the clinical interpretation of the results.
A large open, parallel, single, and observational cohort study carried out by Geleris et al. (2020) Paulo Michel Pinheiro Ferreira, Rayran Walter Ramos de Sousa, Dalton Dittz, João Marcelo de Castro e Sousa, Francisco Leonardo Torres-Leal, Daniel Pereira Bezerra with 1,376 patients, demonstrated that there was no association between HCQ and a lower rate of intubation or death in patients with COVID-19.As assumed by the authors, the results do not support the use of HCQ outside randomized clinical trials.Intriguingly, the decision to prescribe HCQ and/or azithromycin was given to the medical staff for each patient without clear rules.Patients who had already used sarilumab also received HCQ.In addition to the 27 patients who received remdesivir as a compassionate drug, thirty patients had already been included in a randomized, cohort, double-blind clinical trial with sarilumab.Therefore, some patients received 3 different treatments simultaneously.This study has 2 strong points: i) the statistical adjustment to reduce confounding factors for age, race, ethnicity, body mass index, diabetes, underlying kidney disease, chronic lung disease, hypertension, vital signs baseline, PaO 2 :FIO 2 (oxygen arterial pressure:inspired fraction of oxygen) and inflammatory markers, although these inflammatory markers were not discussed in the article; ii) the use of propensity-score methods to reduce the effects of confounding because of the nonrandomized treatment.
In New York, a clinical trial conducted with 1,438 patients receiving HCQ, azithromycin, or both did not exhibit a reduction in lethality in hospitalized patients and revealed that cardiac arrest events were more frequent in HCQ plus azithromycin-treated patients than in those who did not receive such medications (Rosenberg et al., 2020).This report of HCQ-related side effects in patients with COVID-19 was obtained in a cohort, retrospective, multicenter, and observational analysis in 25 hospitals in New York state and supplemented by medical record reviews by trained chart abstractors.These data represented 88.2% of patients hospitalized in the region and provided good analysis of the heterogeneity of different communities and hospital protocols.Considering the innate complexity of this large clinical trial, some issues deserve to be highlighted.Data (deaths and side effects) were collected, as seen for most clinical studies conducted thus far, only from hospitalized patients.The necessity for intensive care unit (ICU) admission, mechanical ventilation or any treatment occurred shortly after admittance to the hospital, which impaired monitoring and time analysis and ICU admission-related factors and ventilation requirements.Although the supplementary material shows the use of NSAIDs (aspirin, celecoxib, diclofenac, ibuprofen, indomethacin, naproxen, oxaprazine, piroxicam) by patients who did not receive HCQ or azithromycin, patients receiving aspirin only (19.8%, 38/198) represented the most significant percentage of the volunteers.However, some people were also using the angiotensin-converting enzyme (ACE) inhibitor lisinopril (6.7%, 13/193) and the angiotensin receptor blocker losartan (2.6%, 5/192).As described in Borba et al. (2020), this study assumed a mortality rate of 20% in the group that did not receive HCQ. Interestingly, this study used statistical tools to control bias involving risk factors [≥ 65 years old, sex, diabetes, chronic lung disease, cardiovascular diseases (hypertension, coronary artery disease, congestive heart failure)] and the severity of signs and symptoms [respiratory rate > 22/min, O 2 saturation < 90%, abnormal chest imaging findings, aspartate aminotransferase (AST > 40 U/L and elevated creatinine levels)].
A multicenter, randomized, open controlled clinical trial in 16 hospitals from three Chinese provinces with 150 patients found no additional benefits of virus elimination after adding HCQ to the standard treatment of patients with moderate COVID-19 symptoms (Tang et al., 2020).A longer follow-up period up to 28 days (up to 7 days after the last dose of HCQ) was the main strength of the study, including visits that allowed the analysis of vital signs, functional biochemical markers, alterations and pulmonary symptoms, and side effects.This study focused on male patients (82%) with about 46 years-old and mild or moderate symptoms (99%; 1% with severe symptoms only), which explains, at least in part, the absence of COVID-19 progress/regression assessments.Another important difference from previous studies was that treatment with HCQ started 16 days after symptom onset, but this seems to not influence viral conversion results.A serious but inconclusive issue was that higher doses (1200 mg/day of HCQ for 3 days, followed by a maintenance dose of 800 mg/ day) for longer periods compared to previous clinical trials (14 days) did not cause deaths during the clinical trial.As expected, this finding is certainly related to the clinical profile of patients: most of them presented mild to moderate symptoms, which implied that highest doses of HCQ would not cause better antiviral effects, since self-healing is a well-established process in these cases.A critical methodology decision to require two consecutive molecular tests for SARS-CoV-2 with a 24-h interval to reduce the possibility of false negative outcomes and the presence of an independent security monitoring committee that supervised, reviewed and performed periodic statistical analysis of the project, gave greater credibility to the results.Million et al. (2020) conducted a single, retrospective, uncontrolled, and descriptive study that recommends generalized usage of HCQ, even in mild cases.They reached this conclusion based on tomographic scores.Most patients (948 = 97.4%)showed a low national early warning score [NEWS < 4)] on admission to the hospital, suggesting that the majority of patients present a mild form of the disease at the beginning of treatment around the 6 th day after the onset of symptoms, whose outcomes were confirmed by radiological findings.On the other hand, medical follow-up by computed tomography revealed that 36% had normal lungs, 43.2% showed minimal pulmonary impairment, and 19.2% had intermediate impairment.Bilaterally lung injuries were not mentioned.It is worth mentioning the inclusion of young people between 14 and 18 years old and the exclusion of patients with a risk of unpleasant side effects: cardiac complications (33 patients), likely pharmacological interaction with CQ/HCQ (15), hypokalemia (10), contraindications (6), allergy to HCQ + azithromycin (4), gastrointestinal tract intolerance to HCQ + azithromycin (4), and nonrecommended patients (66 were classified as nonspecific/no extra details were available).Broad-spectrum antibiotics (ceftriaxone or ertapenem) were routinely given to the patients with pneumonia and NEWS ≥ 5, and such interaction was not weighed.
At that time, Gautret et al. (2020b) suggested that the coadministration of HCQ sulfate and azithromycin can be used to treat and cure patients at early stages of COVID-19 before irreversible respiratory complications and to decrease or prevent the spread of the disease based mainly on viral conversion on days 7 (66/80 = 83%) and 9 (75/80 = 93%).However, there was no control group for comparison, and just one arm was included, whose patients received 200 mg of HCQ 3 times daily for 3 days plus azithromycin (500 mg on day 1 followed by 250 mg per day for 4 days).In this retrospective, descriptive, and observational analysis at a French hospital, they did not notice important adverse effects after drug exposure.Only 15% had fever, a rare finding since most previous pathological follow-ups display fever as one of the most characteristic symptoms in moderate to severe patients (Chen et al., 2020;Huang et al., 2020;Xie et al., 2020).Most (71.2%) were aged < 60 years, 5% of the patients were asymptomatic, 53.8% reported symptoms of lower respiratory tract infection, and 41.2% had symptoms of upper respiratory tract infection.Thus, nearly half of them had mild disease, although the National Early Warning Score (NEWS) interpretation was aberrantly high (92%, see Table I).The NEWS is a tool developed by the Royal College of Physicians at the National Health System of England to detect and respond to clinical deterioration in adult patients and is a key element of patient safety and improving patient outcomes.
On the other hand, patients receiving oral HCQ 200-400 mg/day to treat SLE for approximately 7.5 years have not demonstrated prophylactic protection against COVID-19 (Mathian et al., 2020).This small, descriptive, observational, nonrandomized single trial with SLE patients infected with COVID-19 also reports that, with the exception of a higher rate of dyspnea, headache, and diarrhea, the signs and symptoms of COVID-19 were similar to those described for people without SLE.This indicates that clinical follow-up and updated standard SLE therapy prevent acute attacks of SLE in patients with COVID-19, but it does not prevent COVID-19 progression from the viral to the inflammatory phase, even with HCQ plasma concentrations within the therapeutic range.In addition, among the 17 patients, 14 used prednisolone, 7 used immunosuppressants (5, mycophenolate mofetil; 2, methotrexate), 6 patients used ACE inhibitors, and 5 used anticoagulants.Fifth-three percent received antibiotics, although bacterial infection has been detected in just one (Mathian et al., 2020).The continuous use of corticosteroids by these patients also Paulo Michel Pinheiro Ferreira, Rayran Walter Ramos de Sousa, Dalton Dittz, João Marcelo de Castro e Sousa, Francisco Leonardo Torres-Leal, Daniel Pereira Bezerra raises the discussion about the premature use of steroids to prevent the progression and worsening of COVID-19.
An observational, multicenter, nonrandomized, and controlled study in four French higher education hospitals, with patients aged 60 years, of which 72% were men, showed that HCQ did not reduce ICU admission or deaths until the 21 st day after admission or ARDS in hospitalized patients with hypoxemic COVID-19 pneumonia (Mahévas et al., 2020).Starting the treatment 48 h after hospitalization was a differential of the study because attacking the infection early has been critical for reducing viral load and could have a clinical benefit if began before 12 days after the onset of symptoms (Cao et al., 2020).The average interval between the onset of symptoms and hospitalization was 7 days, much earlier than in the study of Tang et al. (2020), but the decision to treat or not treat patients with HCQ was based on local medical consensus and personal opinions of physicians.This subjective aspect and lack of unanimity for therapy was certainly a confusing factor.To avoid loss of monitoring due to transferences to another hospital, hospital-hospital contacts were produced to obtain outcomes.However, this study does not declare if there was loss to follow-up or how many patients dropped out.The clinical features of the patients were consistent with other descriptions, such as the predominance of men and patients with cardiovascular comorbidities and obesity (Million et al., 2020;Tang et al., 2020), and they did not receive steroidal or nonsteroidal anti-inflammatory drugs before transference to the ICU, especially because nonsteroidal anti-inflammatory drugs (such as antipyretics) for adults are contraindicated for COVID-19 patients in France.Nevertheless, 18 and 76% of the patients belonging to the HCQ group and 52% and 28% in the control group received azithromycin and amoxicillin plus clavulanic acid, respectively, an appropriate clinical supportive treatment in cases of secondary bacterial pneumonia.
In the United States, a cohort multicenter study was designed to assess records from the integrated medical centers of the Veterans Health Administration of the United States (Magagnoli et al., 2020).Since 91% of all US veterans are male, the findings were influenced by the demographic composition (Garg et al., 2020): men, most black, with an average ranging between 68 and 71 years for our groups.After adjusting for several relevant confounders, no benefit from HCQ groups with or without azithromycin was observed in relation to survival outcomes, the need for mechanical ventilation, or length of stay among hospitalized COVID-19 patients.Despite limitations such as lack of randomization typical for retrospective studies, a total of 19 confounding relevant factors were statistically adjusted, including comorbidities, medications, and clinical and laboratory changes.In this context, it is important to highlight the high percentage of patients with diabetes (with or without complications) (534/807 = 66%), nephropathies, chronic cardiovascular (346/807 = 43%) and pulmonary (175/807 = 21.7%)diseases and cancers (127/807 = 15.7%) in all groups, in addition to the presence of smokers (128/807 = 15.9%) and hyperlipidemic individuals (124/807 = 15.4%).Clinically, the oxygen saturation was below 94% in 33.6%, ALT was > 40 U/L in 24.8%, and D-dimer was > 1000 ng/ mL in 22.9% of the patients.These laboratory values at baseline were significantly different among the treatment groups, with the HQC and HQC + azithromycin groups having more patients with elevated hepatic enzymes and inflammatory markers.All received support therapy, but the study did not report which drugs were part of such therapy.Of out 807 patients, 121 (15%) and 67 (8.3%) were taking angiotensin converting enzyme inhibitors and angiotensin II receptor blockers, respectively.Since additional ventilation was not required in the group that received HCQ, it suggests that mortality in this group can be attributed to the side effects effects of treatment or to the disfunction in vital nonrespiratory organ systems.Considering the applicability for the general population, the main limitation of this study lies in the fact that it was done with older hospitalized men, which makes it a challenge to extrapolate some results to women and younger hospitalized persons or to pediatric patients.Another borderline factor for extrapolation is the disproportionality of blacks, but this directly reflects higher rates of COVID-19-related hospitalization among the black population in the United States during the first wave of the disease.This became clear throughout the year and now it is known that race and ethnicity are risk factors that affect health in USA, since American Indian or Alaska Native, Black or African American and Hispanic, or Latino persons have as much as 3.5, 2.8, and 3-fold higher probability to need hospitalization and are 2.4, 1.9, and 2.3 more susceptible to die of COVID-19, especially because race and ethnicity are risk markers for other underlying conditions that affect health, including socioeconomic status, access to health care, and exposure to the virus related to occupation, e.g., frontline, frontline and essential infrastrutcture workers (COVID-NET, 2020; CDC, 2021).
A large and controversial obser vational, nonrandomized, multiracial, multicenter and intercontinental clinical trial analyzed, for a period of 4 months, data from patients admitted to 671 hospitals on 6 continents.Based on the results obtained at that time using artificial intelligence technological tools, the authors stated that there were no clinical benefits of CQ and HCQ alone or in combination with a macrolide.Additionally, such combination schedules were associated with an increased risk of ventricular arrhythmias and hospital death in patients with COVID-19 (Mehra et al., 2020).With an average age of approximately 55 years for all groups, the majority of patients were white (probable due to the greater number of patients from the USA).Data were collected in urban and rural, academic or community hospitals and in for-profit and nonprofit hospitals, which provided great heterogeneity of patients and generated significant population representativeness of the results.The standardization of clinical and laboratory signals of COVID-19, following the WHO guidelines, allowed us to reduce biases for the confirmation of COVID-19.Based on the underlying comorbidities described in the electronic medical record of each patient or hospital, in addition to exposure to treatment, the highest risk of death was associated with age > 60 years, obesity, male sex, body mass index > 30 kg/m 2 , black or Hispanic ethnicity, diabetes, hyperlipidemia, coronary artery disease, congestive heart failure, immunosuppression, history of arrhythmias, chronic obstructive pulmonary disease, cigarettes, and SPO 2 < 94%.On the other hand, relevant data showed that women, people who use ACE inhibitors and statins and those with quick sequential organ failure assessment scores (qSOFA) < 1 had superior hospital survival.qSOFA is a bedside prompt that may identify patients with suspected infection who are at greater risk for a poor outcome outside the intensive care unit (ICU).It is used to assess the severity of organ dysfunction in a potentially septic patient: pressure (systolic blood pressure ≤ 100 mmHg), respiratory rate (≥ 22 breaths/min), or alterations of the central nervous system (Glasgow coma scale < 15) (Marik, Taeb, 2017).Each component allocated one point.Therefore, a qSOFA score of ≥ 2 points indicates organ dysfunction/failure.
In these retrospective investigations, Mehra et al. (2020) also suggested that drugs that stabilize cardiovascular and endothelial function may improve the prognosis and that ACE inhibitors and statins will be pharmacological classes with cardioprotective properties for patients with COVID-19.However, the study did not determine whether the association of an increased risk of hospital death with the use of medication regimens is directly related to cardiovascular risk, and a complete analysis of the dose response of risks was not performed.A few days after publication and enquiries, the authors published a note stating that an internal audit would not guarantee the veracity of primary data sources, since the company responsible for collecting and processing the raw data did not go through all the information required for a careful and independent analysis.Therefore, this article was retracted (Mehra et al., 2020).However, most of the findings detailed here were demonstrated in further controlled prospective clinical trials.
With prophylactic purposes, a prospective, multicenter, double-blind, placebo-randomized clinical trial was carried out with patients aged 40 years using 600 to 800 mg of HCQ sulfate daily for 5 days.Enrolled patients exhibited a low prevalence (< 30%) of chronic diseases (hypertension, diabetes and asthma) within four days after contact with sources of domestic or occupational contamination (Boulware et al., 2020).Considering that the risk for developing severe COVID-19 is related to age and coexisting pathological conditions, this study evaluated the risk of acquiring symptomatic infection, since this risk proved to be the same among adults, regardless of age.A question of great concern consisted that the majority (66.4%) of the participants were health professionals, which implies a high risk of contagion for 2/3 of the sample, and a high percentage of them (~ 60%) did not report using any Paulo Michel Pinheiro Ferreira, Rayran Walter Ramos de Sousa, Dalton Dittz, João Marcelo de Castro e Sousa, Francisco Leonardo Torres-Leal, Daniel Pereira Bezerra personal protective equipment (PPE) during exposure to COVID-19.For health professionals, exposure was predominantly associated with sick patients (76.7%) or infected coworkers (19.6%).Patients were followed-up until the 14 th day, which allowed to detect symptomatic volunteers.In this case, they basically showed similar symptoms as previously described (Huang et al., 2020;Qiu et al., 2020;Yang et al., 2020;Zheng et al., 2020), including predominance of cough, fever, increased breathing, fatigue, sore throat, myalgia, and anosmia.In addition, the survey included up to 6 weeks of followup to detect any illness or hospitalization.Treatment adherence was lower in the HCQ group, probably because 40.1% (140 of 349) reported nausea, loose stools and abdominal discomfort as the most common side effects on the fifth day of treatment.As stated by the authors, cardiac arrhythmias or serious intervention-related adverse reactions were not detected, but it is important to highlight: the study does not report cardiac exams, such as electrocardiograms.
An inter national multicenter study was conducted with symptomatic, nonhospitalized adults with laboratory-confirmed COVID-19 or probable COVID-19 and high-risk exposure within 4 days of symptom onset (Skipper et al., 2020).Doses based on pharmacokinetic parameters to achieve and maintain HCQ sulfate concentrations above the estimated halfmaximal effective concentration (EC 50 ) for SARS- CoV-2 (Al-Kofahi et al., 2020) revealed that HCQ was not able to reduce symptom severity.Only 12% in average improvement was detected, a modest clinical outcome when compared to other antiviral drugs against influenza, for example (Nicholson et al., 2000;Treanor et al., 2000).In addition, a difference in symptoms was not observed when the comparisons were limited to fever, cough, or breath changes at day 14 (16% for HCQ vs. 22% for placebo).An extra discovery involves the use of zinc or vitamin C plus hydroxychloroquine: they did not improve symptoms over the use of HCQ alone (Skipper et al., 2020).An essential methodology question must be highlighted: the double-blind placebo-controlled trial with a parallel design was categorically effective to reveal that adverse effects markedly differed between groups despite HCQ had not substantially substantially reduced symptom severity or prevalence over time in nonhospitalized persons with early COVID-19.Skipper et al. (2020) designed a randomized doubleblind placebo-controlled trial study with outpatient adults and concluded that self-reported use of zinc or vitamin C in addition to HCQ did not decrease symptom prevalence or severity over the 14-day study period.Between groups, there were no significant differences in age, sex, weight, comorbidities, duration, type or number of symptoms (p > 0.05), but persons identified as Black or African American were underrepresented (3%).Participants were younger when compared with other investigations, since 77% of them were under 50 years old and had few comorbid conditions, a disadvantage when generalization of results is wished.A remarkable limitation includes the absence of confirmed SARS-CoV-2 infection in all patients, although they met international and U.S. COVID-19 case definitions.As described in Table 1, gastrointestinal symptoms were the most commonly reported adverse effects in 31% (66 of 212) of participants, who reported upset stomach or nausea, and 24% (50 of 212) cited abdominal pain, diarrhea, or vomiting.The prevalence of such adverse effects decreased markedly after day 5 (last day for HCQ).
An American comparative, retrospective, nonblinded cohort study with patients presenting a median age of 64 years, 51% male, 56% African American, and accompanied for 28.5 days (IQR 3-53) indicated that HCQ may have a role in reducing COVID-19 mortality (Arshad et al. 2020).The majority of patients (52%, n = 1.250) had a body mass index ≥ 30, hypertension (65.4%), chronic kidney disease (43.3%), and diabetes mellitus (37.6%).A maximum SOFA score > 1 (2-5) was found for 73.6%, and O 2 saturation on admission of 90% was seen in all groups.An important reason for confounding considered a supporter therapy with corticosteroids (methylprednisolone and/or prednisone) and anti-IL-6 tocilizumab provided for 68% and 4.5% of patients, respectively.They monitored patients by telemetry and serial QTc checks; torsades de pointes were not documented, and even patients with severe COVID-19 and QTc > 500 ms (an elevated cardiac risk) were treated with HCQ and/or azithromycin.Nevertheless, cardiac arrest (with a mean QTc interval from the last ECG reading 471 ms) was the primary cause of mortality for 18 out of 460 deaths.The strengths of this study include the inclusion of a multiracial composition of volunteers and control of confounding factors, including clinical characteristics, but the results are not confirmed by previous retrospective investigations with patients under similar clinical conditions (Geleris et al., 2020;Rosenberg et al., 2020).Such results should be interpreted with some caution and should not be applied to patients treated outside of hospital settings (Arshad et al. 2020).
The outcomes obtained by Arshad et al. (2020) were sharply criticized by Varisco et al. (2020) and Atkinson (2020) because i) the use of corticosteroids was common in patients who received HCQ with or without azithromycin (79% and 74%, respectively), but such adjunctive therapy was not disclosed, which strongly indicates that an initial clinical decline in HCQ arms was masked by corticosteroids; ii) dichotomizing age was alarming, given the established association between COVID-19 mortality and age; iii) Arshad et al. (2020) did not include azithromycin as a covariate in the propensity scored model (Varisco et al., 2020); iv) the volunteers were consciously allocated to the treatment protocols based on their basic pathological conditions, a bias not adjusted; v) they found COVID-19 increased risk of death due to cardiovascular comorbidities at 6 %, BMI of 30 or higher reduces the patient's risk of death by 22%, and being white increases it by 74%; vi) they make extensive adjustments to the death rate if the patient receives ventilator support, masking the real necessity of the HCQ group (Atkinson, 2020).
A well-designed multicenter randomized (1:1), openlabel controlled trial in Catalonia (Spain) was mainly made up of healthcare workers [254 (86.7% of 293)] and did not find virologic or clinical benefit of HCQ in ambulatorial patients with mild COVID-19 if HCQ sulfate was initiated within five days from symptom onset.The quantification of the viral load in the upper URT provides strong evidence on the capacity of the treatment to affect the pathogen burden.Moreover, this treatment regimen neither reduced the risk of hospitalization nor decreased the time to complete resolution of symptoms (Mitjá et al., 2020).As expected, the volunteers were younger (mean age of 41.6 years), which explains the absence of deaths and the necessity of mechanical ventilation.Similarities in age, comorbidities, frequency of symptoms, and nasopharyngeal viral load were maintained from baseline to the 28 th day of monitoring, and fever, cough, and sudden olfactory loss were the most common symptoms.The most frequent treatment-related adverse effects among participants receiving HCQ were gastrointestinal (e.g., diarrhea, nausea, metallic taste, and abdominal pain) and nervous system disorders (e.g., drowsiness and headache).
In Brazil, a large interventionist trial named "Coalition Covid-19 Brazil I", characterized by a multicenter, randomized (1:1:1), open-label, and controlled study, was performed in 55 hospitals from all Brazilian regions (Cavalcanti et al., 2020).Most patients (584/665 = 87.8%)underwent randomization within 10 days after symptom onset, and almost half of them (42%) were receiving supplemental oxygen at baseline.It revealed that hospitalized patients with mild-to-moderate COVID-19 did not present clinical benefits after a 7-day course of HCQ and/or azithromycin when compared with the standard care.After 15 days, 68%, 64% and 69% of control, HCQ, and HCQ + azithromycin patients, respectively, were comparably discharged, and no difference in the return of routine activities was observed.There was no medical consensus for standard care, which certainly had strong influence on the outcomes but confounding factors were not statistically assessed: > 50% of the patients received ceftriaxone, > 20% were exposed to oseltamivir or antibiotics not mentioned, and approximately 20% were also treated with corticosteroids.
On the other hand, analyses of patients with rheumatic disease receiving long-term HCQ considering serum and plasma, frozen serum samples from a pediatric systemic lupus erythematosus trial, and in silico simulated concentrations using a pharmacokinetic model during pregnancy found that most patients, including children and pregnant/nonpregnant adults, do not achieve adequate serumserum concentrations to inhibit SARS-CoV-2 in vitro, especially at standard dosages < 400 mg/day (400 mg orally every 24 h for 5 days is the standard-of-care dosing for most patients with rheumatic diseases) (Balevic et al., 2020).This showed only one-tenth or less exposure than that required for in vitro for in vitro viral inhibition, Paulo Michel Pinheiro Ferreira, Rayran Walter Ramos de Sousa, Dalton Dittz, João Marcelo de Castro e Sousa, Francisco Leonardo Torres-Leal, Daniel Pereira Bezerra and it would not achieve median target exposures reported by Gautret et al. (2020a) and Yao et al. (2020), but longlasting exposure exerts a suppressive effect on interleukin 6 (IL-6) levels, possibly by affecting macrophage/ monocyte release as opposed to lymphocyte-released cytokines (Wallace et al., 1994;Jang et al., 2006).
Drugs that decrease the viral index may be inappropriate when administered in the inflammatory phase during the called 'cytokine storm', generally on the second to third week after the manifestation of COVID-19 symptoms.Despite the immunomodulatory properties of HCQ, including the control of proinflammatory cytokines, such as IL-1, IL-2, IL-6, and TNFα, and inhibition of important reactions for the innate immune response, such as the endolysosomal physiological process of Toll-like receptors (Schrezenmeier, Dörner, 2020;Ferreira et al., 2021), treatment with HCQ has not shown clinical efficacy against the advanced inflammatory phase of the disease, mainly for hospitalized patients (Borba et al., 2020;Cao et al., 2020;Geleris et al., 2020;Mahévas et al., 2020;Magagnoli et al., 2020;Molina et al., 2020;Rosenberg et al., 2020) or mild-to-moderate COVID-19 (Skipper et al., 2020;Cavalcanti et al., 2020;Mitjà et al., 2020;Tang et al., 2020).Moreover, it seems unable to prevent COVID-19 infection or the progression of COVID-19 in patients who have been taken antimalarials chronically to treat autoimmune diseases (Balevic et al., 2020;Mathian et al., 2020).In 2018, investigations paradoxically showed that prophylactic treatment with CQ enhances Chikungunya virus replication in a nonhuman primate model, probably due to the downregulation of cellular and humoral immune system components (Roques et al., 2018), with similar results for patients.
As described in different studies, nearly 80% of patients with COVID-19 confirmed by RT-PCR tests are asymptomatic; 20% are symptomatic, of which 81% will have mild or moderate disease, 14% will have severe pneumonia and will need hospitalization, and approximately 5% will be severely affected and will require intensive care (Chen et al., 2020;Huang et al., 2020;Wu, McGoogan, 2020).While the global lethality of COVID-19 does not exceed 3%, it is appropriate to state that 97% of symptomatic patients will fully recover without antiviral treatment.Therefore, if a protocol was implemented for free prescription and universal use of CQ or HCQ (with or without azithromycin) for all symptomatic patients, the real effectiveness would be significant if the cure rate reached values greater than 97% (BSI, 2020).Therefore, even during the first wave, many results clearly indicated the use of CQ and HCQ with or without macrolides in clinical trials only, preferably randomized, double-or triple-blind trials, with control/placebo, and multicentric arms involving public and private institutions to represent, understand and cover regional, ethnic and gender differences, and with a representative number of volunteers clinically classified by disease severity.
Robust qualitative and quantitative studies have suggested caution when using CQ or HCQ plus azithromycin/clarithromycin or f luoroquinolones (ciprofloxacin, norfloxacin) since these drugs may increase the risk of cardiac complications due to synergistic effects for prolonging the QT interval and the onset arrhythmias and heart block (Borba et al., 2020;Mahévas et al., 2020;Rosenberg et al., 2020).CQ, HCQ, amodiaquine, and other aminoquinolines in clinical use clearly cause blurred vision, metallic taste, upset stomach or nausea, abdominal pain, diarrhea, and vomiting (Braga, Valle, 2007;Srinivasa, Tosounidou, Gordon, 2017;Mitjá et al., 2020;Skipper et al., 2020;Tang et al., 2020).Specifically, at loading doses > 800 mg, nervous system disorders, including drowsiness, agitation, insomnia, confusion, headache, hallucinations, paranoia, depression, catatonia, and suicide intention, were registered (Mitjá et al., 2020; Spanish Agency of Drug and Health Products, 2020); hypoglycemia due to the action of aminoquinolines (important in diabetics) (Schrezenmeier, Dörner, 2020), and clinical condition aggravation of patients with cardiovascular and kidney diseases (Borba et al., 2020;Rosenberg et al., 2020).Retinopathy is very common when aminoquinolines are chronically used (Schrezenmeier, Dörner, 2020), but behavior disorders may appear at any age, during acute or chronic use, and in patients without a history of psychiatric illness (Spanish Agency of Drug and Health Products, 2020).
Azithromycin and clarithromycin are the most commonly used antimicrobial macrolides and have a broad spectrum of action against common bacteria in respiratory, enteric and genitourinary infections (Parnham et al., 2014).Azithromycin also has antiinflammatory activity by inhibiting the production of GM-CSF and IL-β1 (Bosnar et al., 2009) and the enzyme phospholipase A 2 (PLA 2 ) (Banjanac et al., 2012).Nevertheless, there are insufficient data demonstrating the benefits of antibiotic therapy in patients with COVID-19 without bacterial infection.Indeed, there is no scientific evidence indicating such clinical protocols and large-scale usage of antibiotics may favor the development of microbial resistance, especially when they are administered to immunosuppressed patients due to the early use of steroids (Parnham et al., 2014;Tang et al., 2019;Brasil, 2020;Geleris et al., 2020;Molina et al., 2020;Million et al., 2020).
Viral conversion (negative results detected by RT-PCR), a basic finding to confirm cure, was not found in most clinical trials published until July 2020 after treatment with HCQ, and mortality is probably associated with CQ/HCQ with or without azithromycin, probably due to increases in the QTc interval (Bessière et al., 2020;Borba et al., 2020;Cavalcanti et al., 2020;Mercuro et al., 2020;Singh et al., 2020).This may be explained, at least in part, because extracellular lung concentrations do not reach effective concentrations.Indeed, computational simulations had already suggested in April 2020 that higher doses for treatment and prophylactic purposes would be mandatory (higher doses than those recommended for malaria) (Al-Kofahi et al., 2020).Hence, 200 mg three times daily is inappropriate to reach a supposed target blood level of 1-2 mg/L (Perinel et al., 2020), a likely interval estimated for EC 50 blood levels to present virustatic/virucidal effects for CQ and HCQ (Wang et al., 2020;Yao et al., 2020).These findings were consistent with the > 20-fold lower in vitro EC 50 for malaria compared with SARS-CoV-2 (Al-Kofahi et al., 2020), strongly indicating that treatment with CQ or HCQ has low potential for in vivo activity at standard dosing regimens (Fan et al., 2020).Furthermore, findings indicate that a concentration of 2 mg/L should not be exceeded to avoid ocular toxicity (Perinel et al., 2020), and physiological changes in infused, ventilated patients with multiple organ failure may modify HCQ pharmacokinetic parameters (Tukacs, 2018;Perinel et al., 2020).
On June 05, 2020, a large multicenter, multinational and randomized trial with several clinical arms (Randomized Evaluation of COVID-19 thERapY -RECOVERY) was partially cancelled for ethical reasons, since the HCQ arm displayed a lack of clinical effectiveness.In addition to HCQ and azithromycin, this study included lopinavir-ritonavir, dexamethasone, tocilizumab, and plasma from convalescent patients.This decision was based on partial results (80% of them), whose 1542 patients receiving HCQ, when compared to 3132 who received supportive treatment (control group), did not show a significant reduction in mortality, need for mechanical ventilation, or days of hospitalization after 28 days of follow-up (RECOVERY, 2020).Some months later, they concluded that HCQ was not superior to usual care and did not improve survival among patients hospitalized with COVID-19 infection.Additionally, patients receiving HCQ showed a longer duration of hospitalization than those receiving usual care (16 days vs. 13 days) and a worse probability of discharge alive within 28 days (59.6% vs. 62.9%)(The RECOVERY Collaborative Group, 2020).
By June 15, 2020, the FDA revoked the emergency authorization for CQ and HCQ to treat COVID-19 in hospitalized patients because large randomized clinical trials with hospitalized patients showed no benefit for decreasing the likelihood of death or speeding recovery (FDA, 2020).Corroborating these decisions, the WHO also discontinued the trial's HCQ and lopinavir/ritonavir arms in the Solidarity Trial because these drugs produce little or no reduction in mortality in hospitalized COVID-19 patients when compared to standard care (WHO, 2020a).Next, they published a complete report showing that remdesivir, HCQ, lopinavir, and interferon regimens did not reduce mortality overall and had no effects on the initiation of ventilation or duration of hospitalization (WHO Solidarity Trial Consortium et al., 2021).Therefore, it became clear that thousands of patients have received HCQ and CQ outside of clinical trials without evidence of beneficial effects.
Precisely about the Brazilian situation, surveys have demonstrated that Brazil performed approximately 11.3 RT-PCR tests per 100,000 inhabitants (Resende, 2021).This low coverage has been associated with the Paulo Michel Pinheiro Ferreira, Rayran Walter Ramos de Sousa, Dalton Dittz, João Marcelo de Castro e Sousa, Francisco Leonardo Torres-Leal, Daniel Pereira Bezerra off-label use of drugs (Borba et al., 2020;Cavalcanti et al., 2020;Cardoso, Fernandes, Santos, 2021) and vitamins (Skipper et al., 2020) without scientific evidence, late adoption of sanitary emergencies (Aquino et al., 2020), noncoordinated national/regional interventions, flow disruption of federal financial transfers and essential supplies, absence of national rules based on scientific decisions (Ferigato et al., 2020), late governmental financial support for social isolation and purposeful dissemination of fake news.These issues and the political polarization certainty subsidized anti-vaccination movements, the propagation of SARS-CoV-2 (Guimarães et al., 2020;Toueg, 2021), the encouragement to ignore social isolation or wear face masks, stimulated the emergence of new variants and strains (WHO, 2020b;Sabino et al., 2021), and contributed to the depletion of medications for effective intubation (Bergamo, 2021) and for the collapse of the Brazilian Public Health System (Sistema Único de Saúde, SUS) (Ranzani et al., 2021).
Since the general public has given much attention to the COVID-19 pandemic and the search for specific treatments, weak and early evidence about CQ or HCQ is continuously discussed in TV channels and social networks despite the unfavorable results continuously displayed by randomized clinical trials (Axfors et al., 2021).Inside the storm of misinformation, key preclinical and clinical steps for the development and use of pharmaceutical products were relativized during the first wave of COVID-19 to save time, material, and human resources for drug repurposing aiming to reduce the dissemination of SARS-CoV-2.Therefore, not only pharmacodynamic discoveries but also essential data about pharmacokinetic profiles, therapeutic windows, and safety were put on the back burner.However, even for well-described drugs, extrapolation of preclinical experimental pharmacological results to humans is inexact (Clark, Steger-Hartmann, 2018) because of the systemic complexity of metazoan molecular pathways.

CONCLUSION AND FINAL CONSIDERATIONS
Chloroquine and hydroxychloroquine (with or without macrolides) did not demonstrate clinical advantages that justified their inclusion in therapeutic regimens of free prescription for the treatment of patients infected with COVID-19 or with prophylactic purposes, as suggested by some countries and authorities, including in Brazil, during the first wave.Most trials did not include children or pregnant/breastfeeding women and had a low capacity to understand the role of comorbid conditions and ethnicity as risk factors, which undoubtedly makes extrapolation difficult for the general population.
Although CQ and HCQ have received extraordinary attention as potential therapeutic agents after some inconclusive preclinical investigations and clinical trials, around August 2020, robust data had already indicated that pharmacological effects of CQ, HCQ, and macrolides as anti-SARS-CoV-2 molecules were limited to in vitro conditions and were largely based on retrospective clinical studies with low methodological quality and weak internal validity, which made evidence superficial for decision-making.Up to that point, most randomized and nonrandomized clinical trials did not reveal beneficial effects of CQ or HCQ with or without macrolides to reduce lethality, rate of intubation, days of hospitalization, respiratory support/mechanical ventilation requirements, duration, type and number of symptoms, and death and were unsuccessful in increasing virus elimination and/or days alive in hospitalized or ambulatory patients with COVID-19.Furthermore, many studies have demonstrated that side effects are more common in CQ-or HCQ-treated individuals, mainly in hospitalized patients, including cardiovascular and gastrointestinal alterations.Almost three years after the World Health Organization declared COVID-19 a public health emergency of international concern, the reduction of symptom severity and hospitalizations, adoption of sanitary emergencies, social isolation, and, more recently, preventive vaccination campaigns have been the key public mitigation strategies to overcome the SARS-CoV-2 pandemic since no specific and effective antiviral drugs have been discovered to date.

FIGURE 2 -
FIGURE 2 -General flowchart of the research process, screening and eligibility of articles to compose the results and the discussion of the thematic proposal.

TABLE I -
Details about clinical trials with chloroquine or hydroxychloroquine during the first wave of the COVID-19 pandemic.

TABLE I -
Details about clinical trials with chloroquine or hydroxychloroquine during the first wave of the COVID-19 pandemic.

TABLE I -
Details about clinical trials with chloroquine or hydroxychloroquine during the first wave of the COVID-19 pandemic.Michel Pinheiro Ferreira, Rayran Walter Ramos de Sousa, Dalton Dittz, João Marcelo de Castro e Sousa, Francisco Leonardo Torres-Leal, Daniel Pereira Bezerra Paulo

TABLE I -
Details about clinical trials with chloroquine or hydroxychloroquine during the first wave of the COVID-19 pandemic.

TABLE I -
Details about clinical trials with chloroquine or hydroxychloroquine during the first wave of the COVID-19 pandemic.

TABLE I -
Details about clinical trials with chloroquine or hydroxychloroquine during the first wave of the COVID-19 pandemic.

TABLE I -
Details about clinical trials with chloroquine or hydroxychloroquine during the first wave of the COVID-19 pandemic.Michel Pinheiro Ferreira, Rayran Walter Ramos de Sousa, Dalton Dittz, João Marcelo de Castro e Sousa, Francisco Leonardo Torres-Leal, Daniel Pereira Bezerra Paulo

TABLE I -
Details about clinical trials with chloroquine or hydroxychloroquine during the first wave of the COVID-19 pandemic.