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{"project":"LitCovid-PD-UBERON","denotations":[{"id":"T6","span":{"begin":336,"end":340},"obj":"Body_part"},{"id":"T7","span":{"begin":1758,"end":1762},"obj":"Body_part"},{"id":"T8","span":{"begin":4102,"end":4125},"obj":"Body_part"},{"id":"T9","span":{"begin":4108,"end":4125},"obj":"Body_part"},{"id":"T10","span":{"begin":5921,"end":5932},"obj":"Body_part"},{"id":"T11","span":{"begin":6008,"end":6019},"obj":"Body_part"},{"id":"T12","span":{"begin":11856,"end":11879},"obj":"Body_part"},{"id":"T13","span":{"begin":11862,"end":11879},"obj":"Body_part"},{"id":"T14","span":{"begin":15457,"end":15468},"obj":"Body_part"}],"attributes":[{"id":"A6","pred":"uberon_id","subj":"T6","obj":"http://purl.obolibrary.org/obo/UBERON_0002048"},{"id":"A7","pred":"uberon_id","subj":"T7","obj":"http://purl.obolibrary.org/obo/UBERON_0002048"},{"id":"A8","pred":"uberon_id","subj":"T8","obj":"http://purl.obolibrary.org/obo/UBERON_0001557"},{"id":"A9","pred":"uberon_id","subj":"T9","obj":"http://purl.obolibrary.org/obo/UBERON_0000065"},{"id":"A10","pred":"uberon_id","subj":"T10","obj":"http://purl.obolibrary.org/obo/UBERON_0001728"},{"id":"A11","pred":"uberon_id","subj":"T11","obj":"http://purl.obolibrary.org/obo/UBERON_0001728"},{"id":"A12","pred":"uberon_id","subj":"T12","obj":"http://purl.obolibrary.org/obo/UBERON_0001557"},{"id":"A13","pred":"uberon_id","subj":"T13","obj":"http://purl.obolibrary.org/obo/UBERON_0000065"},{"id":"A14","pred":"uberon_id","subj":"T14","obj":"http://purl.obolibrary.org/obo/UBERON_0001728"}],"text":"5. Clinical efficacy of CQ/HCQ in the treatment of COVID-19\nOnly two published clinical reports have studied the efficacy of CQ in COVID-19 patients (Table 1). One study used CQ to treat more than 100 patients with COVID-19 and claimed that CQ was superior to the control group in suppressing the deterioration of pneumonia, improving lung imaging, promoting viral conversion and shortening the course of disease. Serious adverse effects were not observed in these patients [48]. However, this report did not provide any details about the study design and patient data, thus it is difficult to evaluate the validity. Recently, a parallel, double-blind, randomized, phase IIB clinical trial was performed in Brazil [49]. In this study, 81 severe COVID-19 patients were randomly divided into two groups: 41 patients received high-dose CQ (600 mg/2 times/day for 10 day) and 40 patients received low-dose CQ (450 mg/2 times on day 1 and then 450 mg/1 time/day for 4 days). The 13-day mortality rate in the high-dose group was more than double that in low-dose group (39.0% vs. 16.0%). The high-dosage group exhibited more instance of corrected QT (QTc) interval prolongation (\u003e500 milliseconds (ms); 7 of 37 [18.9%]) than the low-dosage group (4 of 36 [11.1%]). These findings suggest that the higher CQ dosage should not be recommended for critically ill patients with COVID-19 [49].\nTable 1. Outcomes and advantage/limitation of chloroquine (CQ)/hydroxychloroquine (HCQ) clinical studies for COVID-19.\nAuthor (Reference) Study design Patients Treatment Outcomes Advantage Limitations\nGao et al [48]. Rough and simple description Not mentioned CQ (No specific dosage was mentioned) CQ was superior to control in suppressing pneumonia deterioration, improving lung imaging, promoting viral conversion and shortening disease course. Not significant. No study design and the specific number of patients and controls were provided and thus the result appears to be unconvincing.\nBorba et al [49]. Randomized controlled trial High-dose CQ group: n = 40;Low-dose CQ group:n = 41 high-dose CQ (600 mg/2 times/day, for 10 day);low-dose CQ (450 mg/2 times/day for 5 days, double dose on 1st day) The mortality rate in the high-dose group was more than double that in low-dose group Double-blind study; 2 dosages of CQ for the first time in severe COVID-19 Small sample size; single-center design; Lack of a placebo control; Lack of exclusion criteria based on the QTc interval at baseline\nChen et al.[50] Randomized trial HCQ group: n = 31; control group: n = 30 HCQ (200 mg/2 times/day for 5 days) HCQ group have small improvement in body temperature and cough compered with control group Randomized trial. Small sample size; Single-center design; Small improvement in temperature and cough.\nMahévas et al [53]. Comparative study HCQ group: n = 84; control group: n = 97 HCQ 600 mg/day for 7 days Compared with control group, a reduction of admissions to ICU or death 7 days after hospital admission was not observed in HCQ group. Relatively larger sample size in HCQ treatment and control groups. Nonrandomized design; In propensity score model, four possible important prognostic variables were unbalanced.\nTang et al [54]. Open label, randomized controlled trial HCQ group: n = 70; control group: n = 80. HCQ 1200 mg daily for 3 days, 800 mg daily for 2 weeks (mild to moderate disease)/3 weeks(severe disease) HCQ did not show additional benefits of vial elimination in patients with mild to moderate COVID-19. Randomized controlled study. Lack of a placebo control group; Design introduces the possibility of biased investigator determined assessment and unbalanced dosage adjustment; Randomization of sequential envelopes may be biased. The antiviral efficacy of HCQ was not assessed at an earlier stage; Most patients are mild to severe, and the effect of HCQ on disease progression or regression could not be provided. The trial terminated early due to the difficulty to recruit enough patients. Some secondary endpoints could not be analyzed by the cutoff date; Viral RNA specimens are mostly from the upper respiratory tract rather than bronchoalveolar lavage fluid, which may cause false negative results.\nGeleris et al [55]. Observational study HCQ group: n = 811; no-HCQ group: n = 565 HCQ (600 mg/2 times on the first day, then 400 mg once a day for 4 days) No correlation between the HCQ use and significant higher or lower risk of intubation or death was observed. Large sample size; Minimization of the unmeasured confusion and error through multivariable Cox model with inverse probability weighting according to the propensity score. Single-center design; missing of some variables; Potential for inaccuracies in the electronic health records.\nYu et al [56]. Retrospective study HCQ group: n = 48; no-HCQ group: n = 502 HCQ (200 mg/2 times/day, for 7 to 10 days) The fatalities of HCQ group was significantly lower than no-HCQ group. HCQ treatment was related to significantly reduced mortality in critically ill COVID-19 patients and greatly lowered IL-6 level. Mortality was used as a measure of outcome and the study included critically ill patients. Retrospective design of the study and the number of HCQ group patients was small.\nGautret et al.[57] Open label, nonrandom cohort study HCQ group: n = 12; HCQ＋azithromycin group: n = 6; control group: n = 12 HCQ (200 mg/3 times/day for 10 days) HCQ alone or in combination with azithromycin could effectively eliminate nasopharyngeal virus in 3–5 days. Nasopharyngeal virus determination was used as main endpoint. Small sample size; Six patients dropped out due to critical illness or intolerance to the drug; Lack of clinical outcomes; Limited follow-up results.\nGautret et al [58]. Observational study HCQ group: n = 80; no control HCQ, 200 mg/3 times/day for 10 days combined with azithromycin 500 mg on the 1st day, 250 mg/day afterward for 5 days The nasopharynx viral load in most patients received HCQ decreased rapidly. Observation of nasopharynx viral load. Observational study design and no control group; No clinical outcomes were analyzed. Possible confounding factors were not adjusted.\nMagagnoli et al [59]. Retrospective study HCQ group:n = 97HCQ＋azithromycin: n = 113No HCQ group:n = 158 Not specified. The use of HCQ, either with or without azithromycin, didn’t reduce the risk of mechanical ventilation in patients hospitalized with COVID-19; Patients treated with HCQ alone was associated with increased overall mortality. The study data comes from a comprehensive electronic medical record; Strictly defined covariates and outcomes; Using propensity scores adjustment for a large number of relevant confounders to make results more persuasive. Retrospective nature of the study; The subjects included only men and most of them were black; Despite adjustments to many possible confounding factors, there may still be undiscovered factors.\nRosenberg et al[60] Retrospective multicenter cohort study HCQ group:n = 271;HCQ ＋azithromycin group:n = 735control group:n = 221 HCQ:200 mg/400 mg/600 mg/other/unknown, frequency: once a day/twice a day/other/unknownazithromycin:200 mg/250 mg/400 mg/500 mg/other/unknown, methods:Oral/IV/unknown,frequency: only once/once a day/twice a day/other/unknown Treatment with HCQ, azithromycin, or both, compared with neither treatment, was not significantly associated with differences in in-hospital mortality. This study include a large, random sample from 25 metropolitan New York hospitals. The sample was drawnearly in the epidemic to include patients with long, complicated, and ongoing hospital stays; In-hospital mortality was used as primary outcome. Retrospective study design; There may be missing information; Mortality was limited to in-hospital death; There may be potential confounders. The dosing in the doses and frequencies of HCQ and azithromycin varied greatly. The confidence intervals for some of the findings are wide.\nMehraet al[61] Multinational real-world analysis Teatment groups: n = 14,888Control group: n = 81,144 Mean daily dose: CQ 765 mg, (SD 308); HCQ 596 mg(126); CQ with a macrolide 790 mg(320); HCQ with a macrolide 597 mg(128).mean duration:CQ 6.6 days(2.4); HCQ 4.2 days(1.9);CQ with a macrolide 6.8 days(2.5); HCQ with a macrolide 4.3 days (2.0) A benefit of HCQ or CQ, when used alone or witha macrolide, on in-hospital outcomes for COVID-19 was not observed. Large multinational real-world data and large number of study populations. There may be potential confounders; It did not measure QT intervals and stratify the arrhythmia pattern; It did not determine whether the increased risk of death in-hospital and use of drug treatment regimens were directly related to cardiovascular risk; It did not observe the risk of the drug dose-response analysis.\nSeveral trials evaluated the efficacy of HCQ for the treatment of COVID-19 (Table 1). In a randomized clinical trial from Wuhan about HCQ treatment of mild COVID-19 [50], 31 out of 62 patients received HCQ (200 mg/2 times/day for 5 days). The results showed that the temperature recovery time in the HCQ group was improved compared with the control group (average days, 2.2 vs. 3.2); the cough relief time was shorter in the HCQ group than the control group (average days, 2.4 vs. 3.1); and the improvement rate of pneumonia in the HCQ group was higher than the control group (80.6% vs. 54.8%). However, only 48% of patients (15/31) in HCQ group and 71% of patients (22/31) in control group had cough at baseline and the duration of cough was not described. Improvement of symptoms were small and the trial was terminated prematurely. These factors and the low sample size compromise the reliability of the results of this study. Importantly, evaluation of HCQ in the COVID-19 pandemic areas have shown that HCQ can help patients with mild symptoms, and may potentially reduce transmission in areas lacking isolation facilities [51,52]. However, in areas with strict isolation standards, the use of HCQ to reduce transmission or for treatment of mild COVID-19 cases may not be beneficial in risk-benefit analysis [51,52]. Nevertheless, there is an urgent need for drugs and therapeutics in severe cases, which require randomized controlled trials. A study from four French tertiary care centers included 181 patients hospitalized for COVID-19 and requiring oxygen (2 L/min): 84 patients received HCQ (600 mg/day) within 48 hours of admission (HCQ group) and 97 did not (no-HCQ group) [53]. The results showed that the patients transferred to the ICU or died within 7 days and developed ARDS within 7 days had no significant differences between the HCQ group and no-HCQ group. Eight patients in the HCQ group (9.5%) discontinued HCQ due to electrocardiogram alterations. These results do not support the use of HCQ for treating hospitalized COVID-19-related hypoxic pneumonia patients. It is worth noting that in the study’s propensity score model, four possible important prognostic variables were unbalanced and a center effect was not considered, which all can cause bias for study results. In a multicenter, randomized, parallel trial about HCQ in patients with mainly mild to moderate COVID-19 [54], 80 patients received ‘standard care’ and 70 patients received HCQ (1200 mg daily for 3 days, and then 800 mg daily for 2 weeks [mild to moderate disease] or 3 weeks [severe disease]). The results showed that the 28-days negative conversion probability in ‘standard care’＋HCQ group was 85.4%, similar to the ‘standard care’ group (81.2%). HCQ did not show additional benefits of viral elimination in patients with mild to moderate COVID-19. However, the study could not evaluate the antiviral effect of HCQ at early stages of disease, which is a critical period of antiviral treatment. In addition, viral RNA specimens were mostly from the upper respiratory tract rather than bronchoalveolar lavage fluid, which may cause false negative results. Due to the small number of severe patients, this study could not provide evidence regarding the effect of HCQ on the disease progression or regression. In another large observational study involving 1376 cases of COVID-19 from New York, 811 patients received HCQ (600 mg/2 times on the first day, then 400 mg once a day for 4 days) within 24 or 48 hours of admission and 565 did not [55]. This study found no correlation between HCQ use and significantly higher or lower risk of intubation or death. However, in this study, even after the propensity score-matching, the diseases in patients receiving HCQ were more severe at baseline than those in the patients not receiving. Notably, according to another recent study [56], low dose of HCQ reduced fatality of critically ill patients with COVID-19 without apparent toxicity. This retrospective study included 550 patients who need mechanical ventilation, of which 48 received HCQ treatment (200 mg/2 times/day for 7 to 10 days) and 502 did not. The fatalities of the HCQ group was significantly lower than no-HCQ group (18.8% vs 47.4%, P \u003c 0.05), and the inflammatory cytokine IL-6 in the HCQ group decreased significantly from 22.2 (8.3 to 118.9 pg/mL) at the beginning of treatment to 5.2 (3.0 to 23.4 pg/mL) at the end of treatment. The authors deemed that the anti-inflammatory effect of low-dose HCQ and the activity of inhibiting viral replication may have important significance in critically ill patients with COVID-19. Yet, this study is flawed due to its retrospective nature and the small number of HCQ treated patients included. In short, some initial studies have shown that HCQ appears to have a curative effect on patients with mild COVID-19, but subsequent studies indicate that HCQ had no significant benefit in COVID-19 patients with viral conversion and the risk of intubation or death. Although some recent studies show that low-dose HCQ could potentially reduce the mortality of severe COVID-19 patients, there are other studies showing that the HCQ use had no effect on risk of intubation or death.\nThere are also several reports that investigated the efficacy of CQ or HCQ in combination with a macrolide in the treatment of COVID-19 (Table 1). In an open nonrandom clinical trial conducted in France [57], of the 36 participants, 20 patients were given HCQ (200 mg/3 times) with 6 receiving added azithromycin, and 16 controls. The results showed that compared with the control group, HCQ alone or in combination with azithromycin could effectively eliminate nasopharyngeal virus in 3–5 days. On the 6th day after treatment, the virus clearance rates of HCQ combined with azithromycin, HCQ alone and controls were 100%, 57.1% and 12.5%, respectively (P \u003c 0.001). This study indicated that the combined application of azithromycin and HCQ appears to have a synergistic effect. However, the trial design and the results were unreliable, as six patients in the HCQ group discontinued treatment early due to critical illness or intolerance to the drugs and were excluded from the analysis. The assessment of efficacy was based on viral load rather than a clinical endpoint. An observational study in 80 COVID-19 patients evaluated the efficacy of HCQ (200 mg/3 times/day for 10 days) in combination with azithromycin (500 mg on the first day, 250 mg/day afterward for 5 days) and showed that all patients’ clinical symptoms were improved, except for one patient aged over 86 years who died due to critical illness [58]. The nasopharynx viral load in most patients decreased rapidly, and the negative rates of viral nucleic acid conversion on days 7 and 8 were about 83% and 93%, respectively. About 97.5% of patients had negative virus culture in respiratory specimens on the fifth day. However, this study had no control group, thus the results were difficult to interpret [58]. Some recent studies have yielded different results about the efficacy of HCQ combined with azithromycin. A retrospective study including 368 patients (97 patients received HCQ, 113 patients received HCQ + azithromycin and 158 patients received no HCQ) from USA [59] showed that the rates of ventilation in the HCQ, HCQ+azithromycin and no HCQ groups had no significant differences. Unfortunately, theHCQ group (but not in the HCQ+azithromycin group) had a higher risk of death from any case than the no HCQ group. This study showed no evidence that the use of HCQ, either with or without azithromycin, reduced the risk of mechanical ventilation in patients hospitalized with COVID-19. Noticeably, in patients treated with HCQ alone, an association with increased overall mortality was observed [59]. In this study, the subjects included were only men and most of them were black, which may affect the generality of the results. In addition, the patients who received HCQ or azithromycin were more severe, which may also affect the results. In a retrospective multicenter cohort study of a random sample of COVID-19 patients from 25 hospitals in New York [60], totaling 1438 patients, 735 received HCQ and azithromycin, 271 received HCQ alone, 211 received azithromycin alone and 221 received neither drug (HCQ or azithromycin). The results showed that the hospital mortality rate of patients receiving HCQ＋azithromycin was 25.7%, HCQ alone was 19.9%, azithromycin alone was 10.0% and neither drug was 12.7%. In adjusted Cox proportional hazards models, compared with patients receiving neither drug, there were no significant differences in hospital mortality rate for patients receiving HC＋azithromycin, HCQ alone, or azithromycin alone. In this study, the sample size is large and includes patients with long-term, complex and ongoing hospitalization. However, the mortality rate of this study was limited to in-hospital deaths, and patients discharged during the study period were considered alive, which may underestimate the morality rate. Recently, a multinational registry analysis about HCQ or CQ with or without second-generation macrolides (especial azithromycin and clarithromycin) for treatment of COVID-19 was reported [61]. A total of 96,032 patients were included in this study. Of these, 1868 received CQ, 3783 received CQ with a macrolide, 3016 received HCQ and 6221 received HCQ with a macrolide and 8114 patients as control group. After controlling various confounding factors related to disease, when compared with the mortality in the control group (9.3%), CQ group was 16.4%, CQ with a macrolide group was 22.2%, HCQ group was 18.0% and HCQ group with a macrolide was 23.8%; each group was associated with an increased risk of hospital mortality independently. Apart from this, compared with the control group (0.3%), CQ group (4.3%), CQ with a macrolide group (6.5%), HCQ group (6.1%) and HCQ with a macrolide group (8.1%) were independently associated with a risk for ventricular arrhythmia during hospitalization [61]. This study showed that CQ or HCQ (used alone or combination with a macrolide) was associated with an increased hazard for in-hospital death and an increased risk of ventricular arrhythmias. This study included a large number of patients, but it is not a randomized clinical trial. In short, some small studies have shown that HCQ combined with azithromycin could quickly and effectively eliminate viruses, but the design of these studies was flawed in many aspects, making the results unconvincing. Several subsequent studies have shown that the combination of HCQ or CQ and macrolides (azithromycin or clarithromycin) has no obvious correlation with a reduced risk for mechanical ventilation, and may even increase the risk of arrhythmia and in-hospital mortality.\nIn summary, although CQ/HCQ appeared to exhibit a favorable effect on COVID-19 patients in some initial studies of small numbers of patients, the most recent studies with larger sample sizes revealed that CQ/HCQ exhibited no significant improvement of disease but even an increased overall mortality in COVID-19 patients. The studies on the combination of HCQ or CQ and macrolides (azithromycin or clarithromycin) also showed conflicting findings. Therefore, caution should be taken regarding the use of CQ/HCQ treatment in COVID-19 due to the uncertainty of efficacy, the potential adverse effects and the various defects in the studies. According to the Chinese Clinical Trial Registry (ChiCTR) (http://www.chictr.org.cn/index.aspx) and the International Clinical Trials Registry Platform (ICTRP) (https://www.who.int/ictrp/en/), currently, there are more than 200 ongoing clinical trials for CQ/HCQ. Current findings suggest that CQ/HCQ alone or in combination with macrolides should not be recommended for widespread use in COVID-19 (except in clinical trials). Results from these ongoing prospective, randomized, controlled studies are required before these drugs are recommended for the treatment of COVID-19."}

LitCovid-PD-MONDO

LitCovid-PD-CLO

LitCovid-PD-CHEBI

LitCovid-sample-MedDRA

LitCovid-sample-CHEBI

LitCovid-sample-PD-NCBITaxon

LitCovid-sample-sentences

LitCovid-sample-PD-UBERON

{"project":"LitCovid-sample-PD-UBERON","denotations":[{"id":"T6","span":{"begin":336,"end":340},"obj":"Body_part"},{"id":"T7","span":{"begin":1758,"end":1762},"obj":"Body_part"},{"id":"T8","span":{"begin":4102,"end":4125},"obj":"Body_part"},{"id":"T9","span":{"begin":5921,"end":5932},"obj":"Body_part"},{"id":"T10","span":{"begin":6008,"end":6019},"obj":"Body_part"},{"id":"T11","span":{"begin":11856,"end":11879},"obj":"Body_part"},{"id":"T12","span":{"begin":15457,"end":15468},"obj":"Body_part"}],"attributes":[{"id":"A12","pred":"uberon_id","subj":"T12","obj":"http://purl.obolibrary.org/obo/UBERON_0001728"},{"id":"A7","pred":"uberon_id","subj":"T7","obj":"http://purl.obolibrary.org/obo/UBERON_0002048"},{"id":"A8","pred":"uberon_id","subj":"T8","obj":"http://purl.obolibrary.org/obo/UBERON_0001557"},{"id":"A11","pred":"uberon_id","subj":"T11","obj":"http://purl.obolibrary.org/obo/UBERON_0001557"},{"id":"A10","pred":"uberon_id","subj":"T10","obj":"http://purl.obolibrary.org/obo/UBERON_0001728"},{"id":"A9","pred":"uberon_id","subj":"T9","obj":"http://purl.obolibrary.org/obo/UBERON_0001728"},{"id":"A6","pred":"uberon_id","subj":"T6","obj":"http://purl.obolibrary.org/obo/UBERON_0002048"}],"text":"5. Clinical efficacy of CQ/HCQ in the treatment of COVID-19\nOnly two published clinical reports have studied the efficacy of CQ in COVID-19 patients (Table 1). One study used CQ to treat more than 100 patients with COVID-19 and claimed that CQ was superior to the control group in suppressing the deterioration of pneumonia, improving lung imaging, promoting viral conversion and shortening the course of disease. Serious adverse effects were not observed in these patients [48]. However, this report did not provide any details about the study design and patient data, thus it is difficult to evaluate the validity. Recently, a parallel, double-blind, randomized, phase IIB clinical trial was performed in Brazil [49]. In this study, 81 severe COVID-19 patients were randomly divided into two groups: 41 patients received high-dose CQ (600 mg/2 times/day for 10 day) and 40 patients received low-dose CQ (450 mg/2 times on day 1 and then 450 mg/1 time/day for 4 days). The 13-day mortality rate in the high-dose group was more than double that in low-dose group (39.0% vs. 16.0%). The high-dosage group exhibited more instance of corrected QT (QTc) interval prolongation (\u003e500 milliseconds (ms); 7 of 37 [18.9%]) than the low-dosage group (4 of 36 [11.1%]). These findings suggest that the higher CQ dosage should not be recommended for critically ill patients with COVID-19 [49].\nTable 1. Outcomes and advantage/limitation of chloroquine (CQ)/hydroxychloroquine (HCQ) clinical studies for COVID-19.\nAuthor (Reference) Study design Patients Treatment Outcomes Advantage Limitations\nGao et al [48]. Rough and simple description Not mentioned CQ (No specific dosage was mentioned) CQ was superior to control in suppressing pneumonia deterioration, improving lung imaging, promoting viral conversion and shortening disease course. Not significant. No study design and the specific number of patients and controls were provided and thus the result appears to be unconvincing.\nBorba et al [49]. Randomized controlled trial High-dose CQ group: n = 40;Low-dose CQ group:n = 41 high-dose CQ (600 mg/2 times/day, for 10 day);low-dose CQ (450 mg/2 times/day for 5 days, double dose on 1st day) The mortality rate in the high-dose group was more than double that in low-dose group Double-blind study; 2 dosages of CQ for the first time in severe COVID-19 Small sample size; single-center design; Lack of a placebo control; Lack of exclusion criteria based on the QTc interval at baseline\nChen et al.[50] Randomized trial HCQ group: n = 31; control group: n = 30 HCQ (200 mg/2 times/day for 5 days) HCQ group have small improvement in body temperature and cough compered with control group Randomized trial. Small sample size; Single-center design; Small improvement in temperature and cough.\nMahévas et al [53]. Comparative study HCQ group: n = 84; control group: n = 97 HCQ 600 mg/day for 7 days Compared with control group, a reduction of admissions to ICU or death 7 days after hospital admission was not observed in HCQ group. Relatively larger sample size in HCQ treatment and control groups. Nonrandomized design; In propensity score model, four possible important prognostic variables were unbalanced.\nTang et al [54]. Open label, randomized controlled trial HCQ group: n = 70; control group: n = 80. HCQ 1200 mg daily for 3 days, 800 mg daily for 2 weeks (mild to moderate disease)/3 weeks(severe disease) HCQ did not show additional benefits of vial elimination in patients with mild to moderate COVID-19. Randomized controlled study. Lack of a placebo control group; Design introduces the possibility of biased investigator determined assessment and unbalanced dosage adjustment; Randomization of sequential envelopes may be biased. The antiviral efficacy of HCQ was not assessed at an earlier stage; Most patients are mild to severe, and the effect of HCQ on disease progression or regression could not be provided. The trial terminated early due to the difficulty to recruit enough patients. Some secondary endpoints could not be analyzed by the cutoff date; Viral RNA specimens are mostly from the upper respiratory tract rather than bronchoalveolar lavage fluid, which may cause false negative results.\nGeleris et al [55]. Observational study HCQ group: n = 811; no-HCQ group: n = 565 HCQ (600 mg/2 times on the first day, then 400 mg once a day for 4 days) No correlation between the HCQ use and significant higher or lower risk of intubation or death was observed. Large sample size; Minimization of the unmeasured confusion and error through multivariable Cox model with inverse probability weighting according to the propensity score. Single-center design; missing of some variables; Potential for inaccuracies in the electronic health records.\nYu et al [56]. Retrospective study HCQ group: n = 48; no-HCQ group: n = 502 HCQ (200 mg/2 times/day, for 7 to 10 days) The fatalities of HCQ group was significantly lower than no-HCQ group. HCQ treatment was related to significantly reduced mortality in critically ill COVID-19 patients and greatly lowered IL-6 level. Mortality was used as a measure of outcome and the study included critically ill patients. Retrospective design of the study and the number of HCQ group patients was small.\nGautret et al.[57] Open label, nonrandom cohort study HCQ group: n = 12; HCQ＋azithromycin group: n = 6; control group: n = 12 HCQ (200 mg/3 times/day for 10 days) HCQ alone or in combination with azithromycin could effectively eliminate nasopharyngeal virus in 3–5 days. Nasopharyngeal virus determination was used as main endpoint. Small sample size; Six patients dropped out due to critical illness or intolerance to the drug; Lack of clinical outcomes; Limited follow-up results.\nGautret et al [58]. Observational study HCQ group: n = 80; no control HCQ, 200 mg/3 times/day for 10 days combined with azithromycin 500 mg on the 1st day, 250 mg/day afterward for 5 days The nasopharynx viral load in most patients received HCQ decreased rapidly. Observation of nasopharynx viral load. Observational study design and no control group; No clinical outcomes were analyzed. Possible confounding factors were not adjusted.\nMagagnoli et al [59]. Retrospective study HCQ group:n = 97HCQ＋azithromycin: n = 113No HCQ group:n = 158 Not specified. The use of HCQ, either with or without azithromycin, didn’t reduce the risk of mechanical ventilation in patients hospitalized with COVID-19; Patients treated with HCQ alone was associated with increased overall mortality. The study data comes from a comprehensive electronic medical record; Strictly defined covariates and outcomes; Using propensity scores adjustment for a large number of relevant confounders to make results more persuasive. Retrospective nature of the study; The subjects included only men and most of them were black; Despite adjustments to many possible confounding factors, there may still be undiscovered factors.\nRosenberg et al[60] Retrospective multicenter cohort study HCQ group:n = 271;HCQ ＋azithromycin group:n = 735control group:n = 221 HCQ:200 mg/400 mg/600 mg/other/unknown, frequency: once a day/twice a day/other/unknownazithromycin:200 mg/250 mg/400 mg/500 mg/other/unknown, methods:Oral/IV/unknown,frequency: only once/once a day/twice a day/other/unknown Treatment with HCQ, azithromycin, or both, compared with neither treatment, was not significantly associated with differences in in-hospital mortality. This study include a large, random sample from 25 metropolitan New York hospitals. The sample was drawnearly in the epidemic to include patients with long, complicated, and ongoing hospital stays; In-hospital mortality was used as primary outcome. Retrospective study design; There may be missing information; Mortality was limited to in-hospital death; There may be potential confounders. The dosing in the doses and frequencies of HCQ and azithromycin varied greatly. The confidence intervals for some of the findings are wide.\nMehraet al[61] Multinational real-world analysis Teatment groups: n = 14,888Control group: n = 81,144 Mean daily dose: CQ 765 mg, (SD 308); HCQ 596 mg(126); CQ with a macrolide 790 mg(320); HCQ with a macrolide 597 mg(128).mean duration:CQ 6.6 days(2.4); HCQ 4.2 days(1.9);CQ with a macrolide 6.8 days(2.5); HCQ with a macrolide 4.3 days (2.0) A benefit of HCQ or CQ, when used alone or witha macrolide, on in-hospital outcomes for COVID-19 was not observed. Large multinational real-world data and large number of study populations. There may be potential confounders; It did not measure QT intervals and stratify the arrhythmia pattern; It did not determine whether the increased risk of death in-hospital and use of drug treatment regimens were directly related to cardiovascular risk; It did not observe the risk of the drug dose-response analysis.\nSeveral trials evaluated the efficacy of HCQ for the treatment of COVID-19 (Table 1). In a randomized clinical trial from Wuhan about HCQ treatment of mild COVID-19 [50], 31 out of 62 patients received HCQ (200 mg/2 times/day for 5 days). The results showed that the temperature recovery time in the HCQ group was improved compared with the control group (average days, 2.2 vs. 3.2); the cough relief time was shorter in the HCQ group than the control group (average days, 2.4 vs. 3.1); and the improvement rate of pneumonia in the HCQ group was higher than the control group (80.6% vs. 54.8%). However, only 48% of patients (15/31) in HCQ group and 71% of patients (22/31) in control group had cough at baseline and the duration of cough was not described. Improvement of symptoms were small and the trial was terminated prematurely. These factors and the low sample size compromise the reliability of the results of this study. Importantly, evaluation of HCQ in the COVID-19 pandemic areas have shown that HCQ can help patients with mild symptoms, and may potentially reduce transmission in areas lacking isolation facilities [51,52]. However, in areas with strict isolation standards, the use of HCQ to reduce transmission or for treatment of mild COVID-19 cases may not be beneficial in risk-benefit analysis [51,52]. Nevertheless, there is an urgent need for drugs and therapeutics in severe cases, which require randomized controlled trials. A study from four French tertiary care centers included 181 patients hospitalized for COVID-19 and requiring oxygen (2 L/min): 84 patients received HCQ (600 mg/day) within 48 hours of admission (HCQ group) and 97 did not (no-HCQ group) [53]. The results showed that the patients transferred to the ICU or died within 7 days and developed ARDS within 7 days had no significant differences between the HCQ group and no-HCQ group. Eight patients in the HCQ group (9.5%) discontinued HCQ due to electrocardiogram alterations. These results do not support the use of HCQ for treating hospitalized COVID-19-related hypoxic pneumonia patients. It is worth noting that in the study’s propensity score model, four possible important prognostic variables were unbalanced and a center effect was not considered, which all can cause bias for study results. In a multicenter, randomized, parallel trial about HCQ in patients with mainly mild to moderate COVID-19 [54], 80 patients received ‘standard care’ and 70 patients received HCQ (1200 mg daily for 3 days, and then 800 mg daily for 2 weeks [mild to moderate disease] or 3 weeks [severe disease]). The results showed that the 28-days negative conversion probability in ‘standard care’＋HCQ group was 85.4%, similar to the ‘standard care’ group (81.2%). HCQ did not show additional benefits of viral elimination in patients with mild to moderate COVID-19. However, the study could not evaluate the antiviral effect of HCQ at early stages of disease, which is a critical period of antiviral treatment. In addition, viral RNA specimens were mostly from the upper respiratory tract rather than bronchoalveolar lavage fluid, which may cause false negative results. Due to the small number of severe patients, this study could not provide evidence regarding the effect of HCQ on the disease progression or regression. In another large observational study involving 1376 cases of COVID-19 from New York, 811 patients received HCQ (600 mg/2 times on the first day, then 400 mg once a day for 4 days) within 24 or 48 hours of admission and 565 did not [55]. This study found no correlation between HCQ use and significantly higher or lower risk of intubation or death. However, in this study, even after the propensity score-matching, the diseases in patients receiving HCQ were more severe at baseline than those in the patients not receiving. Notably, according to another recent study [56], low dose of HCQ reduced fatality of critically ill patients with COVID-19 without apparent toxicity. This retrospective study included 550 patients who need mechanical ventilation, of which 48 received HCQ treatment (200 mg/2 times/day for 7 to 10 days) and 502 did not. The fatalities of the HCQ group was significantly lower than no-HCQ group (18.8% vs 47.4%, P \u003c 0.05), and the inflammatory cytokine IL-6 in the HCQ group decreased significantly from 22.2 (8.3 to 118.9 pg/mL) at the beginning of treatment to 5.2 (3.0 to 23.4 pg/mL) at the end of treatment. The authors deemed that the anti-inflammatory effect of low-dose HCQ and the activity of inhibiting viral replication may have important significance in critically ill patients with COVID-19. Yet, this study is flawed due to its retrospective nature and the small number of HCQ treated patients included. In short, some initial studies have shown that HCQ appears to have a curative effect on patients with mild COVID-19, but subsequent studies indicate that HCQ had no significant benefit in COVID-19 patients with viral conversion and the risk of intubation or death. Although some recent studies show that low-dose HCQ could potentially reduce the mortality of severe COVID-19 patients, there are other studies showing that the HCQ use had no effect on risk of intubation or death.\nThere are also several reports that investigated the efficacy of CQ or HCQ in combination with a macrolide in the treatment of COVID-19 (Table 1). In an open nonrandom clinical trial conducted in France [57], of the 36 participants, 20 patients were given HCQ (200 mg/3 times) with 6 receiving added azithromycin, and 16 controls. The results showed that compared with the control group, HCQ alone or in combination with azithromycin could effectively eliminate nasopharyngeal virus in 3–5 days. On the 6th day after treatment, the virus clearance rates of HCQ combined with azithromycin, HCQ alone and controls were 100%, 57.1% and 12.5%, respectively (P \u003c 0.001). This study indicated that the combined application of azithromycin and HCQ appears to have a synergistic effect. However, the trial design and the results were unreliable, as six patients in the HCQ group discontinued treatment early due to critical illness or intolerance to the drugs and were excluded from the analysis. The assessment of efficacy was based on viral load rather than a clinical endpoint. An observational study in 80 COVID-19 patients evaluated the efficacy of HCQ (200 mg/3 times/day for 10 days) in combination with azithromycin (500 mg on the first day, 250 mg/day afterward for 5 days) and showed that all patients’ clinical symptoms were improved, except for one patient aged over 86 years who died due to critical illness [58]. The nasopharynx viral load in most patients decreased rapidly, and the negative rates of viral nucleic acid conversion on days 7 and 8 were about 83% and 93%, respectively. About 97.5% of patients had negative virus culture in respiratory specimens on the fifth day. However, this study had no control group, thus the results were difficult to interpret [58]. Some recent studies have yielded different results about the efficacy of HCQ combined with azithromycin. A retrospective study including 368 patients (97 patients received HCQ, 113 patients received HCQ + azithromycin and 158 patients received no HCQ) from USA [59] showed that the rates of ventilation in the HCQ, HCQ+azithromycin and no HCQ groups had no significant differences. Unfortunately, theHCQ group (but not in the HCQ+azithromycin group) had a higher risk of death from any case than the no HCQ group. This study showed no evidence that the use of HCQ, either with or without azithromycin, reduced the risk of mechanical ventilation in patients hospitalized with COVID-19. Noticeably, in patients treated with HCQ alone, an association with increased overall mortality was observed [59]. In this study, the subjects included were only men and most of them were black, which may affect the generality of the results. In addition, the patients who received HCQ or azithromycin were more severe, which may also affect the results. In a retrospective multicenter cohort study of a random sample of COVID-19 patients from 25 hospitals in New York [60], totaling 1438 patients, 735 received HCQ and azithromycin, 271 received HCQ alone, 211 received azithromycin alone and 221 received neither drug (HCQ or azithromycin). The results showed that the hospital mortality rate of patients receiving HCQ＋azithromycin was 25.7%, HCQ alone was 19.9%, azithromycin alone was 10.0% and neither drug was 12.7%. In adjusted Cox proportional hazards models, compared with patients receiving neither drug, there were no significant differences in hospital mortality rate for patients receiving HC＋azithromycin, HCQ alone, or azithromycin alone. In this study, the sample size is large and includes patients with long-term, complex and ongoing hospitalization. However, the mortality rate of this study was limited to in-hospital deaths, and patients discharged during the study period were considered alive, which may underestimate the morality rate. Recently, a multinational registry analysis about HCQ or CQ with or without second-generation macrolides (especial azithromycin and clarithromycin) for treatment of COVID-19 was reported [61]. A total of 96,032 patients were included in this study. Of these, 1868 received CQ, 3783 received CQ with a macrolide, 3016 received HCQ and 6221 received HCQ with a macrolide and 8114 patients as control group. After controlling various confounding factors related to disease, when compared with the mortality in the control group (9.3%), CQ group was 16.4%, CQ with a macrolide group was 22.2%, HCQ group was 18.0% and HCQ group with a macrolide was 23.8%; each group was associated with an increased risk of hospital mortality independently. Apart from this, compared with the control group (0.3%), CQ group (4.3%), CQ with a macrolide group (6.5%), HCQ group (6.1%) and HCQ with a macrolide group (8.1%) were independently associated with a risk for ventricular arrhythmia during hospitalization [61]. This study showed that CQ or HCQ (used alone or combination with a macrolide) was associated with an increased hazard for in-hospital death and an increased risk of ventricular arrhythmias. This study included a large number of patients, but it is not a randomized clinical trial. In short, some small studies have shown that HCQ combined with azithromycin could quickly and effectively eliminate viruses, but the design of these studies was flawed in many aspects, making the results unconvincing. Several subsequent studies have shown that the combination of HCQ or CQ and macrolides (azithromycin or clarithromycin) has no obvious correlation with a reduced risk for mechanical ventilation, and may even increase the risk of arrhythmia and in-hospital mortality.\nIn summary, although CQ/HCQ appeared to exhibit a favorable effect on COVID-19 patients in some initial studies of small numbers of patients, the most recent studies with larger sample sizes revealed that CQ/HCQ exhibited no significant improvement of disease but even an increased overall mortality in COVID-19 patients. The studies on the combination of HCQ or CQ and macrolides (azithromycin or clarithromycin) also showed conflicting findings. Therefore, caution should be taken regarding the use of CQ/HCQ treatment in COVID-19 due to the uncertainty of efficacy, the potential adverse effects and the various defects in the studies. According to the Chinese Clinical Trial Registry (ChiCTR) (http://www.chictr.org.cn/index.aspx) and the International Clinical Trials Registry Platform (ICTRP) (https://www.who.int/ictrp/en/), currently, there are more than 200 ongoing clinical trials for CQ/HCQ. Current findings suggest that CQ/HCQ alone or in combination with macrolides should not be recommended for widespread use in COVID-19 (except in clinical trials). Results from these ongoing prospective, randomized, controlled studies are required before these drugs are recommended for the treatment of COVID-19."}

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{"project":"LitCovid-sample-PD-MAT","denotations":[{"id":"T4","span":{"begin":336,"end":340},"obj":"http://purl.obolibrary.org/obo/MAT_0000135"},{"id":"T5","span":{"begin":1758,"end":1762},"obj":"http://purl.obolibrary.org/obo/MAT_0000135"},{"id":"T6","span":{"begin":5921,"end":5932},"obj":"http://purl.obolibrary.org/obo/MAT_0000447"},{"id":"T7","span":{"begin":6008,"end":6019},"obj":"http://purl.obolibrary.org/obo/MAT_0000447"},{"id":"T8","span":{"begin":15457,"end":15468},"obj":"http://purl.obolibrary.org/obo/MAT_0000447"}],"text":"5. Clinical efficacy of CQ/HCQ in the treatment of COVID-19\nOnly two published clinical reports have studied the efficacy of CQ in COVID-19 patients (Table 1). One study used CQ to treat more than 100 patients with COVID-19 and claimed that CQ was superior to the control group in suppressing the deterioration of pneumonia, improving lung imaging, promoting viral conversion and shortening the course of disease. Serious adverse effects were not observed in these patients [48]. However, this report did not provide any details about the study design and patient data, thus it is difficult to evaluate the validity. Recently, a parallel, double-blind, randomized, phase IIB clinical trial was performed in Brazil [49]. In this study, 81 severe COVID-19 patients were randomly divided into two groups: 41 patients received high-dose CQ (600 mg/2 times/day for 10 day) and 40 patients received low-dose CQ (450 mg/2 times on day 1 and then 450 mg/1 time/day for 4 days). The 13-day mortality rate in the high-dose group was more than double that in low-dose group (39.0% vs. 16.0%). The high-dosage group exhibited more instance of corrected QT (QTc) interval prolongation (\u003e500 milliseconds (ms); 7 of 37 [18.9%]) than the low-dosage group (4 of 36 [11.1%]). These findings suggest that the higher CQ dosage should not be recommended for critically ill patients with COVID-19 [49].\nTable 1. Outcomes and advantage/limitation of chloroquine (CQ)/hydroxychloroquine (HCQ) clinical studies for COVID-19.\nAuthor (Reference) Study design Patients Treatment Outcomes Advantage Limitations\nGao et al [48]. Rough and simple description Not mentioned CQ (No specific dosage was mentioned) CQ was superior to control in suppressing pneumonia deterioration, improving lung imaging, promoting viral conversion and shortening disease course. Not significant. No study design and the specific number of patients and controls were provided and thus the result appears to be unconvincing.\nBorba et al [49]. Randomized controlled trial High-dose CQ group: n = 40;Low-dose CQ group:n = 41 high-dose CQ (600 mg/2 times/day, for 10 day);low-dose CQ (450 mg/2 times/day for 5 days, double dose on 1st day) The mortality rate in the high-dose group was more than double that in low-dose group Double-blind study; 2 dosages of CQ for the first time in severe COVID-19 Small sample size; single-center design; Lack of a placebo control; Lack of exclusion criteria based on the QTc interval at baseline\nChen et al.[50] Randomized trial HCQ group: n = 31; control group: n = 30 HCQ (200 mg/2 times/day for 5 days) HCQ group have small improvement in body temperature and cough compered with control group Randomized trial. Small sample size; Single-center design; Small improvement in temperature and cough.\nMahévas et al [53]. Comparative study HCQ group: n = 84; control group: n = 97 HCQ 600 mg/day for 7 days Compared with control group, a reduction of admissions to ICU or death 7 days after hospital admission was not observed in HCQ group. Relatively larger sample size in HCQ treatment and control groups. Nonrandomized design; In propensity score model, four possible important prognostic variables were unbalanced.\nTang et al [54]. Open label, randomized controlled trial HCQ group: n = 70; control group: n = 80. HCQ 1200 mg daily for 3 days, 800 mg daily for 2 weeks (mild to moderate disease)/3 weeks(severe disease) HCQ did not show additional benefits of vial elimination in patients with mild to moderate COVID-19. Randomized controlled study. Lack of a placebo control group; Design introduces the possibility of biased investigator determined assessment and unbalanced dosage adjustment; Randomization of sequential envelopes may be biased. The antiviral efficacy of HCQ was not assessed at an earlier stage; Most patients are mild to severe, and the effect of HCQ on disease progression or regression could not be provided. The trial terminated early due to the difficulty to recruit enough patients. Some secondary endpoints could not be analyzed by the cutoff date; Viral RNA specimens are mostly from the upper respiratory tract rather than bronchoalveolar lavage fluid, which may cause false negative results.\nGeleris et al [55]. Observational study HCQ group: n = 811; no-HCQ group: n = 565 HCQ (600 mg/2 times on the first day, then 400 mg once a day for 4 days) No correlation between the HCQ use and significant higher or lower risk of intubation or death was observed. Large sample size; Minimization of the unmeasured confusion and error through multivariable Cox model with inverse probability weighting according to the propensity score. Single-center design; missing of some variables; Potential for inaccuracies in the electronic health records.\nYu et al [56]. Retrospective study HCQ group: n = 48; no-HCQ group: n = 502 HCQ (200 mg/2 times/day, for 7 to 10 days) The fatalities of HCQ group was significantly lower than no-HCQ group. HCQ treatment was related to significantly reduced mortality in critically ill COVID-19 patients and greatly lowered IL-6 level. Mortality was used as a measure of outcome and the study included critically ill patients. Retrospective design of the study and the number of HCQ group patients was small.\nGautret et al.[57] Open label, nonrandom cohort study HCQ group: n = 12; HCQ＋azithromycin group: n = 6; control group: n = 12 HCQ (200 mg/3 times/day for 10 days) HCQ alone or in combination with azithromycin could effectively eliminate nasopharyngeal virus in 3–5 days. Nasopharyngeal virus determination was used as main endpoint. Small sample size; Six patients dropped out due to critical illness or intolerance to the drug; Lack of clinical outcomes; Limited follow-up results.\nGautret et al [58]. Observational study HCQ group: n = 80; no control HCQ, 200 mg/3 times/day for 10 days combined with azithromycin 500 mg on the 1st day, 250 mg/day afterward for 5 days The nasopharynx viral load in most patients received HCQ decreased rapidly. Observation of nasopharynx viral load. Observational study design and no control group; No clinical outcomes were analyzed. Possible confounding factors were not adjusted.\nMagagnoli et al [59]. Retrospective study HCQ group:n = 97HCQ＋azithromycin: n = 113No HCQ group:n = 158 Not specified. The use of HCQ, either with or without azithromycin, didn’t reduce the risk of mechanical ventilation in patients hospitalized with COVID-19; Patients treated with HCQ alone was associated with increased overall mortality. The study data comes from a comprehensive electronic medical record; Strictly defined covariates and outcomes; Using propensity scores adjustment for a large number of relevant confounders to make results more persuasive. Retrospective nature of the study; The subjects included only men and most of them were black; Despite adjustments to many possible confounding factors, there may still be undiscovered factors.\nRosenberg et al[60] Retrospective multicenter cohort study HCQ group:n = 271;HCQ ＋azithromycin group:n = 735control group:n = 221 HCQ:200 mg/400 mg/600 mg/other/unknown, frequency: once a day/twice a day/other/unknownazithromycin:200 mg/250 mg/400 mg/500 mg/other/unknown, methods:Oral/IV/unknown,frequency: only once/once a day/twice a day/other/unknown Treatment with HCQ, azithromycin, or both, compared with neither treatment, was not significantly associated with differences in in-hospital mortality. This study include a large, random sample from 25 metropolitan New York hospitals. The sample was drawnearly in the epidemic to include patients with long, complicated, and ongoing hospital stays; In-hospital mortality was used as primary outcome. Retrospective study design; There may be missing information; Mortality was limited to in-hospital death; There may be potential confounders. The dosing in the doses and frequencies of HCQ and azithromycin varied greatly. The confidence intervals for some of the findings are wide.\nMehraet al[61] Multinational real-world analysis Teatment groups: n = 14,888Control group: n = 81,144 Mean daily dose: CQ 765 mg, (SD 308); HCQ 596 mg(126); CQ with a macrolide 790 mg(320); HCQ with a macrolide 597 mg(128).mean duration:CQ 6.6 days(2.4); HCQ 4.2 days(1.9);CQ with a macrolide 6.8 days(2.5); HCQ with a macrolide 4.3 days (2.0) A benefit of HCQ or CQ, when used alone or witha macrolide, on in-hospital outcomes for COVID-19 was not observed. Large multinational real-world data and large number of study populations. There may be potential confounders; It did not measure QT intervals and stratify the arrhythmia pattern; It did not determine whether the increased risk of death in-hospital and use of drug treatment regimens were directly related to cardiovascular risk; It did not observe the risk of the drug dose-response analysis.\nSeveral trials evaluated the efficacy of HCQ for the treatment of COVID-19 (Table 1). In a randomized clinical trial from Wuhan about HCQ treatment of mild COVID-19 [50], 31 out of 62 patients received HCQ (200 mg/2 times/day for 5 days). The results showed that the temperature recovery time in the HCQ group was improved compared with the control group (average days, 2.2 vs. 3.2); the cough relief time was shorter in the HCQ group than the control group (average days, 2.4 vs. 3.1); and the improvement rate of pneumonia in the HCQ group was higher than the control group (80.6% vs. 54.8%). However, only 48% of patients (15/31) in HCQ group and 71% of patients (22/31) in control group had cough at baseline and the duration of cough was not described. Improvement of symptoms were small and the trial was terminated prematurely. These factors and the low sample size compromise the reliability of the results of this study. Importantly, evaluation of HCQ in the COVID-19 pandemic areas have shown that HCQ can help patients with mild symptoms, and may potentially reduce transmission in areas lacking isolation facilities [51,52]. However, in areas with strict isolation standards, the use of HCQ to reduce transmission or for treatment of mild COVID-19 cases may not be beneficial in risk-benefit analysis [51,52]. Nevertheless, there is an urgent need for drugs and therapeutics in severe cases, which require randomized controlled trials. A study from four French tertiary care centers included 181 patients hospitalized for COVID-19 and requiring oxygen (2 L/min): 84 patients received HCQ (600 mg/day) within 48 hours of admission (HCQ group) and 97 did not (no-HCQ group) [53]. The results showed that the patients transferred to the ICU or died within 7 days and developed ARDS within 7 days had no significant differences between the HCQ group and no-HCQ group. Eight patients in the HCQ group (9.5%) discontinued HCQ due to electrocardiogram alterations. These results do not support the use of HCQ for treating hospitalized COVID-19-related hypoxic pneumonia patients. It is worth noting that in the study’s propensity score model, four possible important prognostic variables were unbalanced and a center effect was not considered, which all can cause bias for study results. In a multicenter, randomized, parallel trial about HCQ in patients with mainly mild to moderate COVID-19 [54], 80 patients received ‘standard care’ and 70 patients received HCQ (1200 mg daily for 3 days, and then 800 mg daily for 2 weeks [mild to moderate disease] or 3 weeks [severe disease]). The results showed that the 28-days negative conversion probability in ‘standard care’＋HCQ group was 85.4%, similar to the ‘standard care’ group (81.2%). HCQ did not show additional benefits of viral elimination in patients with mild to moderate COVID-19. However, the study could not evaluate the antiviral effect of HCQ at early stages of disease, which is a critical period of antiviral treatment. In addition, viral RNA specimens were mostly from the upper respiratory tract rather than bronchoalveolar lavage fluid, which may cause false negative results. Due to the small number of severe patients, this study could not provide evidence regarding the effect of HCQ on the disease progression or regression. In another large observational study involving 1376 cases of COVID-19 from New York, 811 patients received HCQ (600 mg/2 times on the first day, then 400 mg once a day for 4 days) within 24 or 48 hours of admission and 565 did not [55]. This study found no correlation between HCQ use and significantly higher or lower risk of intubation or death. However, in this study, even after the propensity score-matching, the diseases in patients receiving HCQ were more severe at baseline than those in the patients not receiving. Notably, according to another recent study [56], low dose of HCQ reduced fatality of critically ill patients with COVID-19 without apparent toxicity. This retrospective study included 550 patients who need mechanical ventilation, of which 48 received HCQ treatment (200 mg/2 times/day for 7 to 10 days) and 502 did not. The fatalities of the HCQ group was significantly lower than no-HCQ group (18.8% vs 47.4%, P \u003c 0.05), and the inflammatory cytokine IL-6 in the HCQ group decreased significantly from 22.2 (8.3 to 118.9 pg/mL) at the beginning of treatment to 5.2 (3.0 to 23.4 pg/mL) at the end of treatment. The authors deemed that the anti-inflammatory effect of low-dose HCQ and the activity of inhibiting viral replication may have important significance in critically ill patients with COVID-19. Yet, this study is flawed due to its retrospective nature and the small number of HCQ treated patients included. In short, some initial studies have shown that HCQ appears to have a curative effect on patients with mild COVID-19, but subsequent studies indicate that HCQ had no significant benefit in COVID-19 patients with viral conversion and the risk of intubation or death. Although some recent studies show that low-dose HCQ could potentially reduce the mortality of severe COVID-19 patients, there are other studies showing that the HCQ use had no effect on risk of intubation or death.\nThere are also several reports that investigated the efficacy of CQ or HCQ in combination with a macrolide in the treatment of COVID-19 (Table 1). In an open nonrandom clinical trial conducted in France [57], of the 36 participants, 20 patients were given HCQ (200 mg/3 times) with 6 receiving added azithromycin, and 16 controls. The results showed that compared with the control group, HCQ alone or in combination with azithromycin could effectively eliminate nasopharyngeal virus in 3–5 days. On the 6th day after treatment, the virus clearance rates of HCQ combined with azithromycin, HCQ alone and controls were 100%, 57.1% and 12.5%, respectively (P \u003c 0.001). This study indicated that the combined application of azithromycin and HCQ appears to have a synergistic effect. However, the trial design and the results were unreliable, as six patients in the HCQ group discontinued treatment early due to critical illness or intolerance to the drugs and were excluded from the analysis. The assessment of efficacy was based on viral load rather than a clinical endpoint. An observational study in 80 COVID-19 patients evaluated the efficacy of HCQ (200 mg/3 times/day for 10 days) in combination with azithromycin (500 mg on the first day, 250 mg/day afterward for 5 days) and showed that all patients’ clinical symptoms were improved, except for one patient aged over 86 years who died due to critical illness [58]. The nasopharynx viral load in most patients decreased rapidly, and the negative rates of viral nucleic acid conversion on days 7 and 8 were about 83% and 93%, respectively. About 97.5% of patients had negative virus culture in respiratory specimens on the fifth day. However, this study had no control group, thus the results were difficult to interpret [58]. Some recent studies have yielded different results about the efficacy of HCQ combined with azithromycin. A retrospective study including 368 patients (97 patients received HCQ, 113 patients received HCQ + azithromycin and 158 patients received no HCQ) from USA [59] showed that the rates of ventilation in the HCQ, HCQ+azithromycin and no HCQ groups had no significant differences. Unfortunately, theHCQ group (but not in the HCQ+azithromycin group) had a higher risk of death from any case than the no HCQ group. This study showed no evidence that the use of HCQ, either with or without azithromycin, reduced the risk of mechanical ventilation in patients hospitalized with COVID-19. Noticeably, in patients treated with HCQ alone, an association with increased overall mortality was observed [59]. In this study, the subjects included were only men and most of them were black, which may affect the generality of the results. In addition, the patients who received HCQ or azithromycin were more severe, which may also affect the results. In a retrospective multicenter cohort study of a random sample of COVID-19 patients from 25 hospitals in New York [60], totaling 1438 patients, 735 received HCQ and azithromycin, 271 received HCQ alone, 211 received azithromycin alone and 221 received neither drug (HCQ or azithromycin). The results showed that the hospital mortality rate of patients receiving HCQ＋azithromycin was 25.7%, HCQ alone was 19.9%, azithromycin alone was 10.0% and neither drug was 12.7%. In adjusted Cox proportional hazards models, compared with patients receiving neither drug, there were no significant differences in hospital mortality rate for patients receiving HC＋azithromycin, HCQ alone, or azithromycin alone. In this study, the sample size is large and includes patients with long-term, complex and ongoing hospitalization. However, the mortality rate of this study was limited to in-hospital deaths, and patients discharged during the study period were considered alive, which may underestimate the morality rate. Recently, a multinational registry analysis about HCQ or CQ with or without second-generation macrolides (especial azithromycin and clarithromycin) for treatment of COVID-19 was reported [61]. A total of 96,032 patients were included in this study. Of these, 1868 received CQ, 3783 received CQ with a macrolide, 3016 received HCQ and 6221 received HCQ with a macrolide and 8114 patients as control group. After controlling various confounding factors related to disease, when compared with the mortality in the control group (9.3%), CQ group was 16.4%, CQ with a macrolide group was 22.2%, HCQ group was 18.0% and HCQ group with a macrolide was 23.8%; each group was associated with an increased risk of hospital mortality independently. Apart from this, compared with the control group (0.3%), CQ group (4.3%), CQ with a macrolide group (6.5%), HCQ group (6.1%) and HCQ with a macrolide group (8.1%) were independently associated with a risk for ventricular arrhythmia during hospitalization [61]. This study showed that CQ or HCQ (used alone or combination with a macrolide) was associated with an increased hazard for in-hospital death and an increased risk of ventricular arrhythmias. This study included a large number of patients, but it is not a randomized clinical trial. In short, some small studies have shown that HCQ combined with azithromycin could quickly and effectively eliminate viruses, but the design of these studies was flawed in many aspects, making the results unconvincing. Several subsequent studies have shown that the combination of HCQ or CQ and macrolides (azithromycin or clarithromycin) has no obvious correlation with a reduced risk for mechanical ventilation, and may even increase the risk of arrhythmia and in-hospital mortality.\nIn summary, although CQ/HCQ appeared to exhibit a favorable effect on COVID-19 patients in some initial studies of small numbers of patients, the most recent studies with larger sample sizes revealed that CQ/HCQ exhibited no significant improvement of disease but even an increased overall mortality in COVID-19 patients. The studies on the combination of HCQ or CQ and macrolides (azithromycin or clarithromycin) also showed conflicting findings. Therefore, caution should be taken regarding the use of CQ/HCQ treatment in COVID-19 due to the uncertainty of efficacy, the potential adverse effects and the various defects in the studies. According to the Chinese Clinical Trial Registry (ChiCTR) (http://www.chictr.org.cn/index.aspx) and the International Clinical Trials Registry Platform (ICTRP) (https://www.who.int/ictrp/en/), currently, there are more than 200 ongoing clinical trials for CQ/HCQ. Current findings suggest that CQ/HCQ alone or in combination with macrolides should not be recommended for widespread use in COVID-19 (except in clinical trials). Results from these ongoing prospective, randomized, controlled studies are required before these drugs are recommended for the treatment of COVID-19."}

LitCovid-sample-PD-GO-BP-0

{"project":"LitCovid-sample-PD-GO-BP-0","denotations":[{"id":"T64","span":{"begin":2953,"end":2958},"obj":"http://purl.obolibrary.org/obo/GO_0016265"},{"id":"T65","span":{"begin":4452,"end":4457},"obj":"http://purl.obolibrary.org/obo/GO_0016265"},{"id":"T66","span":{"begin":7777,"end":7782},"obj":"http://purl.obolibrary.org/obo/GO_0016265"},{"id":"T67","span":{"begin":8650,"end":8655},"obj":"http://purl.obolibrary.org/obo/GO_0016265"},{"id":"T68","span":{"begin":12455,"end":12460},"obj":"http://purl.obolibrary.org/obo/GO_0016265"},{"id":"T69","span":{"begin":13338,"end":13366},"obj":"http://purl.obolibrary.org/obo/GO_1903901"},{"id":"T70","span":{"begin":13349,"end":13366},"obj":"http://purl.obolibrary.org/obo/GO_0019058"},{"id":"T71","span":{"begin":13349,"end":13366},"obj":"http://purl.obolibrary.org/obo/GO_0019079"},{"id":"T72","span":{"begin":13812,"end":13817},"obj":"http://purl.obolibrary.org/obo/GO_0016265"},{"id":"T73","span":{"begin":14027,"end":14032},"obj":"http://purl.obolibrary.org/obo/GO_0016265"},{"id":"T74","span":{"begin":16284,"end":16289},"obj":"http://purl.obolibrary.org/obo/GO_0016265"},{"id":"T75","span":{"begin":18991,"end":18996},"obj":"http://purl.obolibrary.org/obo/GO_0016265"}],"text":"5. Clinical efficacy of CQ/HCQ in the treatment of COVID-19\nOnly two published clinical reports have studied the efficacy of CQ in COVID-19 patients (Table 1). One study used CQ to treat more than 100 patients with COVID-19 and claimed that CQ was superior to the control group in suppressing the deterioration of pneumonia, improving lung imaging, promoting viral conversion and shortening the course of disease. Serious adverse effects were not observed in these patients [48]. However, this report did not provide any details about the study design and patient data, thus it is difficult to evaluate the validity. Recently, a parallel, double-blind, randomized, phase IIB clinical trial was performed in Brazil [49]. In this study, 81 severe COVID-19 patients were randomly divided into two groups: 41 patients received high-dose CQ (600 mg/2 times/day for 10 day) and 40 patients received low-dose CQ (450 mg/2 times on day 1 and then 450 mg/1 time/day for 4 days). The 13-day mortality rate in the high-dose group was more than double that in low-dose group (39.0% vs. 16.0%). The high-dosage group exhibited more instance of corrected QT (QTc) interval prolongation (\u003e500 milliseconds (ms); 7 of 37 [18.9%]) than the low-dosage group (4 of 36 [11.1%]). These findings suggest that the higher CQ dosage should not be recommended for critically ill patients with COVID-19 [49].\nTable 1. Outcomes and advantage/limitation of chloroquine (CQ)/hydroxychloroquine (HCQ) clinical studies for COVID-19.\nAuthor (Reference) Study design Patients Treatment Outcomes Advantage Limitations\nGao et al [48]. Rough and simple description Not mentioned CQ (No specific dosage was mentioned) CQ was superior to control in suppressing pneumonia deterioration, improving lung imaging, promoting viral conversion and shortening disease course. Not significant. No study design and the specific number of patients and controls were provided and thus the result appears to be unconvincing.\nBorba et al [49]. Randomized controlled trial High-dose CQ group: n = 40;Low-dose CQ group:n = 41 high-dose CQ (600 mg/2 times/day, for 10 day);low-dose CQ (450 mg/2 times/day for 5 days, double dose on 1st day) The mortality rate in the high-dose group was more than double that in low-dose group Double-blind study; 2 dosages of CQ for the first time in severe COVID-19 Small sample size; single-center design; Lack of a placebo control; Lack of exclusion criteria based on the QTc interval at baseline\nChen et al.[50] Randomized trial HCQ group: n = 31; control group: n = 30 HCQ (200 mg/2 times/day for 5 days) HCQ group have small improvement in body temperature and cough compered with control group Randomized trial. Small sample size; Single-center design; Small improvement in temperature and cough.\nMahévas et al [53]. Comparative study HCQ group: n = 84; control group: n = 97 HCQ 600 mg/day for 7 days Compared with control group, a reduction of admissions to ICU or death 7 days after hospital admission was not observed in HCQ group. Relatively larger sample size in HCQ treatment and control groups. Nonrandomized design; In propensity score model, four possible important prognostic variables were unbalanced.\nTang et al [54]. Open label, randomized controlled trial HCQ group: n = 70; control group: n = 80. HCQ 1200 mg daily for 3 days, 800 mg daily for 2 weeks (mild to moderate disease)/3 weeks(severe disease) HCQ did not show additional benefits of vial elimination in patients with mild to moderate COVID-19. Randomized controlled study. Lack of a placebo control group; Design introduces the possibility of biased investigator determined assessment and unbalanced dosage adjustment; Randomization of sequential envelopes may be biased. The antiviral efficacy of HCQ was not assessed at an earlier stage; Most patients are mild to severe, and the effect of HCQ on disease progression or regression could not be provided. The trial terminated early due to the difficulty to recruit enough patients. Some secondary endpoints could not be analyzed by the cutoff date; Viral RNA specimens are mostly from the upper respiratory tract rather than bronchoalveolar lavage fluid, which may cause false negative results.\nGeleris et al [55]. Observational study HCQ group: n = 811; no-HCQ group: n = 565 HCQ (600 mg/2 times on the first day, then 400 mg once a day for 4 days) No correlation between the HCQ use and significant higher or lower risk of intubation or death was observed. Large sample size; Minimization of the unmeasured confusion and error through multivariable Cox model with inverse probability weighting according to the propensity score. Single-center design; missing of some variables; Potential for inaccuracies in the electronic health records.\nYu et al [56]. Retrospective study HCQ group: n = 48; no-HCQ group: n = 502 HCQ (200 mg/2 times/day, for 7 to 10 days) The fatalities of HCQ group was significantly lower than no-HCQ group. HCQ treatment was related to significantly reduced mortality in critically ill COVID-19 patients and greatly lowered IL-6 level. Mortality was used as a measure of outcome and the study included critically ill patients. Retrospective design of the study and the number of HCQ group patients was small.\nGautret et al.[57] Open label, nonrandom cohort study HCQ group: n = 12; HCQ＋azithromycin group: n = 6; control group: n = 12 HCQ (200 mg/3 times/day for 10 days) HCQ alone or in combination with azithromycin could effectively eliminate nasopharyngeal virus in 3–5 days. Nasopharyngeal virus determination was used as main endpoint. Small sample size; Six patients dropped out due to critical illness or intolerance to the drug; Lack of clinical outcomes; Limited follow-up results.\nGautret et al [58]. Observational study HCQ group: n = 80; no control HCQ, 200 mg/3 times/day for 10 days combined with azithromycin 500 mg on the 1st day, 250 mg/day afterward for 5 days The nasopharynx viral load in most patients received HCQ decreased rapidly. Observation of nasopharynx viral load. Observational study design and no control group; No clinical outcomes were analyzed. Possible confounding factors were not adjusted.\nMagagnoli et al [59]. Retrospective study HCQ group:n = 97HCQ＋azithromycin: n = 113No HCQ group:n = 158 Not specified. The use of HCQ, either with or without azithromycin, didn’t reduce the risk of mechanical ventilation in patients hospitalized with COVID-19; Patients treated with HCQ alone was associated with increased overall mortality. The study data comes from a comprehensive electronic medical record; Strictly defined covariates and outcomes; Using propensity scores adjustment for a large number of relevant confounders to make results more persuasive. Retrospective nature of the study; The subjects included only men and most of them were black; Despite adjustments to many possible confounding factors, there may still be undiscovered factors.\nRosenberg et al[60] Retrospective multicenter cohort study HCQ group:n = 271;HCQ ＋azithromycin group:n = 735control group:n = 221 HCQ:200 mg/400 mg/600 mg/other/unknown, frequency: once a day/twice a day/other/unknownazithromycin:200 mg/250 mg/400 mg/500 mg/other/unknown, methods:Oral/IV/unknown,frequency: only once/once a day/twice a day/other/unknown Treatment with HCQ, azithromycin, or both, compared with neither treatment, was not significantly associated with differences in in-hospital mortality. This study include a large, random sample from 25 metropolitan New York hospitals. The sample was drawnearly in the epidemic to include patients with long, complicated, and ongoing hospital stays; In-hospital mortality was used as primary outcome. Retrospective study design; There may be missing information; Mortality was limited to in-hospital death; There may be potential confounders. The dosing in the doses and frequencies of HCQ and azithromycin varied greatly. The confidence intervals for some of the findings are wide.\nMehraet al[61] Multinational real-world analysis Teatment groups: n = 14,888Control group: n = 81,144 Mean daily dose: CQ 765 mg, (SD 308); HCQ 596 mg(126); CQ with a macrolide 790 mg(320); HCQ with a macrolide 597 mg(128).mean duration:CQ 6.6 days(2.4); HCQ 4.2 days(1.9);CQ with a macrolide 6.8 days(2.5); HCQ with a macrolide 4.3 days (2.0) A benefit of HCQ or CQ, when used alone or witha macrolide, on in-hospital outcomes for COVID-19 was not observed. Large multinational real-world data and large number of study populations. There may be potential confounders; It did not measure QT intervals and stratify the arrhythmia pattern; It did not determine whether the increased risk of death in-hospital and use of drug treatment regimens were directly related to cardiovascular risk; It did not observe the risk of the drug dose-response analysis.\nSeveral trials evaluated the efficacy of HCQ for the treatment of COVID-19 (Table 1). In a randomized clinical trial from Wuhan about HCQ treatment of mild COVID-19 [50], 31 out of 62 patients received HCQ (200 mg/2 times/day for 5 days). The results showed that the temperature recovery time in the HCQ group was improved compared with the control group (average days, 2.2 vs. 3.2); the cough relief time was shorter in the HCQ group than the control group (average days, 2.4 vs. 3.1); and the improvement rate of pneumonia in the HCQ group was higher than the control group (80.6% vs. 54.8%). However, only 48% of patients (15/31) in HCQ group and 71% of patients (22/31) in control group had cough at baseline and the duration of cough was not described. Improvement of symptoms were small and the trial was terminated prematurely. These factors and the low sample size compromise the reliability of the results of this study. Importantly, evaluation of HCQ in the COVID-19 pandemic areas have shown that HCQ can help patients with mild symptoms, and may potentially reduce transmission in areas lacking isolation facilities [51,52]. However, in areas with strict isolation standards, the use of HCQ to reduce transmission or for treatment of mild COVID-19 cases may not be beneficial in risk-benefit analysis [51,52]. Nevertheless, there is an urgent need for drugs and therapeutics in severe cases, which require randomized controlled trials. A study from four French tertiary care centers included 181 patients hospitalized for COVID-19 and requiring oxygen (2 L/min): 84 patients received HCQ (600 mg/day) within 48 hours of admission (HCQ group) and 97 did not (no-HCQ group) [53]. The results showed that the patients transferred to the ICU or died within 7 days and developed ARDS within 7 days had no significant differences between the HCQ group and no-HCQ group. Eight patients in the HCQ group (9.5%) discontinued HCQ due to electrocardiogram alterations. These results do not support the use of HCQ for treating hospitalized COVID-19-related hypoxic pneumonia patients. It is worth noting that in the study’s propensity score model, four possible important prognostic variables were unbalanced and a center effect was not considered, which all can cause bias for study results. In a multicenter, randomized, parallel trial about HCQ in patients with mainly mild to moderate COVID-19 [54], 80 patients received ‘standard care’ and 70 patients received HCQ (1200 mg daily for 3 days, and then 800 mg daily for 2 weeks [mild to moderate disease] or 3 weeks [severe disease]). The results showed that the 28-days negative conversion probability in ‘standard care’＋HCQ group was 85.4%, similar to the ‘standard care’ group (81.2%). HCQ did not show additional benefits of viral elimination in patients with mild to moderate COVID-19. However, the study could not evaluate the antiviral effect of HCQ at early stages of disease, which is a critical period of antiviral treatment. In addition, viral RNA specimens were mostly from the upper respiratory tract rather than bronchoalveolar lavage fluid, which may cause false negative results. Due to the small number of severe patients, this study could not provide evidence regarding the effect of HCQ on the disease progression or regression. In another large observational study involving 1376 cases of COVID-19 from New York, 811 patients received HCQ (600 mg/2 times on the first day, then 400 mg once a day for 4 days) within 24 or 48 hours of admission and 565 did not [55]. This study found no correlation between HCQ use and significantly higher or lower risk of intubation or death. However, in this study, even after the propensity score-matching, the diseases in patients receiving HCQ were more severe at baseline than those in the patients not receiving. Notably, according to another recent study [56], low dose of HCQ reduced fatality of critically ill patients with COVID-19 without apparent toxicity. This retrospective study included 550 patients who need mechanical ventilation, of which 48 received HCQ treatment (200 mg/2 times/day for 7 to 10 days) and 502 did not. The fatalities of the HCQ group was significantly lower than no-HCQ group (18.8% vs 47.4%, P \u003c 0.05), and the inflammatory cytokine IL-6 in the HCQ group decreased significantly from 22.2 (8.3 to 118.9 pg/mL) at the beginning of treatment to 5.2 (3.0 to 23.4 pg/mL) at the end of treatment. The authors deemed that the anti-inflammatory effect of low-dose HCQ and the activity of inhibiting viral replication may have important significance in critically ill patients with COVID-19. Yet, this study is flawed due to its retrospective nature and the small number of HCQ treated patients included. In short, some initial studies have shown that HCQ appears to have a curative effect on patients with mild COVID-19, but subsequent studies indicate that HCQ had no significant benefit in COVID-19 patients with viral conversion and the risk of intubation or death. Although some recent studies show that low-dose HCQ could potentially reduce the mortality of severe COVID-19 patients, there are other studies showing that the HCQ use had no effect on risk of intubation or death.\nThere are also several reports that investigated the efficacy of CQ or HCQ in combination with a macrolide in the treatment of COVID-19 (Table 1). In an open nonrandom clinical trial conducted in France [57], of the 36 participants, 20 patients were given HCQ (200 mg/3 times) with 6 receiving added azithromycin, and 16 controls. The results showed that compared with the control group, HCQ alone or in combination with azithromycin could effectively eliminate nasopharyngeal virus in 3–5 days. On the 6th day after treatment, the virus clearance rates of HCQ combined with azithromycin, HCQ alone and controls were 100%, 57.1% and 12.5%, respectively (P \u003c 0.001). This study indicated that the combined application of azithromycin and HCQ appears to have a synergistic effect. However, the trial design and the results were unreliable, as six patients in the HCQ group discontinued treatment early due to critical illness or intolerance to the drugs and were excluded from the analysis. The assessment of efficacy was based on viral load rather than a clinical endpoint. An observational study in 80 COVID-19 patients evaluated the efficacy of HCQ (200 mg/3 times/day for 10 days) in combination with azithromycin (500 mg on the first day, 250 mg/day afterward for 5 days) and showed that all patients’ clinical symptoms were improved, except for one patient aged over 86 years who died due to critical illness [58]. The nasopharynx viral load in most patients decreased rapidly, and the negative rates of viral nucleic acid conversion on days 7 and 8 were about 83% and 93%, respectively. About 97.5% of patients had negative virus culture in respiratory specimens on the fifth day. However, this study had no control group, thus the results were difficult to interpret [58]. Some recent studies have yielded different results about the efficacy of HCQ combined with azithromycin. A retrospective study including 368 patients (97 patients received HCQ, 113 patients received HCQ + azithromycin and 158 patients received no HCQ) from USA [59] showed that the rates of ventilation in the HCQ, HCQ+azithromycin and no HCQ groups had no significant differences. Unfortunately, theHCQ group (but not in the HCQ+azithromycin group) had a higher risk of death from any case than the no HCQ group. This study showed no evidence that the use of HCQ, either with or without azithromycin, reduced the risk of mechanical ventilation in patients hospitalized with COVID-19. Noticeably, in patients treated with HCQ alone, an association with increased overall mortality was observed [59]. In this study, the subjects included were only men and most of them were black, which may affect the generality of the results. In addition, the patients who received HCQ or azithromycin were more severe, which may also affect the results. In a retrospective multicenter cohort study of a random sample of COVID-19 patients from 25 hospitals in New York [60], totaling 1438 patients, 735 received HCQ and azithromycin, 271 received HCQ alone, 211 received azithromycin alone and 221 received neither drug (HCQ or azithromycin). The results showed that the hospital mortality rate of patients receiving HCQ＋azithromycin was 25.7%, HCQ alone was 19.9%, azithromycin alone was 10.0% and neither drug was 12.7%. In adjusted Cox proportional hazards models, compared with patients receiving neither drug, there were no significant differences in hospital mortality rate for patients receiving HC＋azithromycin, HCQ alone, or azithromycin alone. In this study, the sample size is large and includes patients with long-term, complex and ongoing hospitalization. However, the mortality rate of this study was limited to in-hospital deaths, and patients discharged during the study period were considered alive, which may underestimate the morality rate. Recently, a multinational registry analysis about HCQ or CQ with or without second-generation macrolides (especial azithromycin and clarithromycin) for treatment of COVID-19 was reported [61]. A total of 96,032 patients were included in this study. Of these, 1868 received CQ, 3783 received CQ with a macrolide, 3016 received HCQ and 6221 received HCQ with a macrolide and 8114 patients as control group. After controlling various confounding factors related to disease, when compared with the mortality in the control group (9.3%), CQ group was 16.4%, CQ with a macrolide group was 22.2%, HCQ group was 18.0% and HCQ group with a macrolide was 23.8%; each group was associated with an increased risk of hospital mortality independently. Apart from this, compared with the control group (0.3%), CQ group (4.3%), CQ with a macrolide group (6.5%), HCQ group (6.1%) and HCQ with a macrolide group (8.1%) were independently associated with a risk for ventricular arrhythmia during hospitalization [61]. This study showed that CQ or HCQ (used alone or combination with a macrolide) was associated with an increased hazard for in-hospital death and an increased risk of ventricular arrhythmias. This study included a large number of patients, but it is not a randomized clinical trial. In short, some small studies have shown that HCQ combined with azithromycin could quickly and effectively eliminate viruses, but the design of these studies was flawed in many aspects, making the results unconvincing. Several subsequent studies have shown that the combination of HCQ or CQ and macrolides (azithromycin or clarithromycin) has no obvious correlation with a reduced risk for mechanical ventilation, and may even increase the risk of arrhythmia and in-hospital mortality.\nIn summary, although CQ/HCQ appeared to exhibit a favorable effect on COVID-19 patients in some initial studies of small numbers of patients, the most recent studies with larger sample sizes revealed that CQ/HCQ exhibited no significant improvement of disease but even an increased overall mortality in COVID-19 patients. The studies on the combination of HCQ or CQ and macrolides (azithromycin or clarithromycin) also showed conflicting findings. Therefore, caution should be taken regarding the use of CQ/HCQ treatment in COVID-19 due to the uncertainty of efficacy, the potential adverse effects and the various defects in the studies. According to the Chinese Clinical Trial Registry (ChiCTR) (http://www.chictr.org.cn/index.aspx) and the International Clinical Trials Registry Platform (ICTRP) (https://www.who.int/ictrp/en/), currently, there are more than 200 ongoing clinical trials for CQ/HCQ. Current findings suggest that CQ/HCQ alone or in combination with macrolides should not be recommended for widespread use in COVID-19 (except in clinical trials). Results from these ongoing prospective, randomized, controlled studies are required before these drugs are recommended for the treatment of COVID-19."}

LitCovid-sample-PD-MONDO

LitCovid-sample-PD-HP

LitCovid-sample-GO-BP

{"project":"LitCovid-sample-GO-BP","denotations":[{"id":"T60","span":{"begin":4184,"end":4189},"obj":"http://purl.obolibrary.org/obo/GO_0071878"},{"id":"T61","span":{"begin":4184,"end":4189},"obj":"http://purl.obolibrary.org/obo/GO_0071877"},{"id":"T62","span":{"begin":11938,"end":11943},"obj":"http://purl.obolibrary.org/obo/GO_0071878"},{"id":"T63","span":{"begin":11938,"end":11943},"obj":"http://purl.obolibrary.org/obo/GO_0071877"},{"id":"T64","span":{"begin":13338,"end":13366},"obj":"http://purl.obolibrary.org/obo/GO_1903901"},{"id":"T65","span":{"begin":13349,"end":13366},"obj":"http://purl.obolibrary.org/obo/GO_0019079"},{"id":"T66","span":{"begin":13349,"end":13366},"obj":"http://purl.obolibrary.org/obo/GO_0019058"}],"text":"5. Clinical efficacy of CQ/HCQ in the treatment of COVID-19\nOnly two published clinical reports have studied the efficacy of CQ in COVID-19 patients (Table 1). One study used CQ to treat more than 100 patients with COVID-19 and claimed that CQ was superior to the control group in suppressing the deterioration of pneumonia, improving lung imaging, promoting viral conversion and shortening the course of disease. Serious adverse effects were not observed in these patients [48]. However, this report did not provide any details about the study design and patient data, thus it is difficult to evaluate the validity. Recently, a parallel, double-blind, randomized, phase IIB clinical trial was performed in Brazil [49]. In this study, 81 severe COVID-19 patients were randomly divided into two groups: 41 patients received high-dose CQ (600 mg/2 times/day for 10 day) and 40 patients received low-dose CQ (450 mg/2 times on day 1 and then 450 mg/1 time/day for 4 days). The 13-day mortality rate in the high-dose group was more than double that in low-dose group (39.0% vs. 16.0%). The high-dosage group exhibited more instance of corrected QT (QTc) interval prolongation (\u003e500 milliseconds (ms); 7 of 37 [18.9%]) than the low-dosage group (4 of 36 [11.1%]). These findings suggest that the higher CQ dosage should not be recommended for critically ill patients with COVID-19 [49].\nTable 1. Outcomes and advantage/limitation of chloroquine (CQ)/hydroxychloroquine (HCQ) clinical studies for COVID-19.\nAuthor (Reference) Study design Patients Treatment Outcomes Advantage Limitations\nGao et al [48]. Rough and simple description Not mentioned CQ (No specific dosage was mentioned) CQ was superior to control in suppressing pneumonia deterioration, improving lung imaging, promoting viral conversion and shortening disease course. Not significant. No study design and the specific number of patients and controls were provided and thus the result appears to be unconvincing.\nBorba et al [49]. Randomized controlled trial High-dose CQ group: n = 40;Low-dose CQ group:n = 41 high-dose CQ (600 mg/2 times/day, for 10 day);low-dose CQ (450 mg/2 times/day for 5 days, double dose on 1st day) The mortality rate in the high-dose group was more than double that in low-dose group Double-blind study; 2 dosages of CQ for the first time in severe COVID-19 Small sample size; single-center design; Lack of a placebo control; Lack of exclusion criteria based on the QTc interval at baseline\nChen et al.[50] Randomized trial HCQ group: n = 31; control group: n = 30 HCQ (200 mg/2 times/day for 5 days) HCQ group have small improvement in body temperature and cough compered with control group Randomized trial. Small sample size; Single-center design; Small improvement in temperature and cough.\nMahévas et al [53]. Comparative study HCQ group: n = 84; control group: n = 97 HCQ 600 mg/day for 7 days Compared with control group, a reduction of admissions to ICU or death 7 days after hospital admission was not observed in HCQ group. Relatively larger sample size in HCQ treatment and control groups. Nonrandomized design; In propensity score model, four possible important prognostic variables were unbalanced.\nTang et al [54]. Open label, randomized controlled trial HCQ group: n = 70; control group: n = 80. HCQ 1200 mg daily for 3 days, 800 mg daily for 2 weeks (mild to moderate disease)/3 weeks(severe disease) HCQ did not show additional benefits of vial elimination in patients with mild to moderate COVID-19. Randomized controlled study. Lack of a placebo control group; Design introduces the possibility of biased investigator determined assessment and unbalanced dosage adjustment; Randomization of sequential envelopes may be biased. The antiviral efficacy of HCQ was not assessed at an earlier stage; Most patients are mild to severe, and the effect of HCQ on disease progression or regression could not be provided. The trial terminated early due to the difficulty to recruit enough patients. Some secondary endpoints could not be analyzed by the cutoff date; Viral RNA specimens are mostly from the upper respiratory tract rather than bronchoalveolar lavage fluid, which may cause false negative results.\nGeleris et al [55]. Observational study HCQ group: n = 811; no-HCQ group: n = 565 HCQ (600 mg/2 times on the first day, then 400 mg once a day for 4 days) No correlation between the HCQ use and significant higher or lower risk of intubation or death was observed. Large sample size; Minimization of the unmeasured confusion and error through multivariable Cox model with inverse probability weighting according to the propensity score. Single-center design; missing of some variables; Potential for inaccuracies in the electronic health records.\nYu et al [56]. Retrospective study HCQ group: n = 48; no-HCQ group: n = 502 HCQ (200 mg/2 times/day, for 7 to 10 days) The fatalities of HCQ group was significantly lower than no-HCQ group. HCQ treatment was related to significantly reduced mortality in critically ill COVID-19 patients and greatly lowered IL-6 level. Mortality was used as a measure of outcome and the study included critically ill patients. Retrospective design of the study and the number of HCQ group patients was small.\nGautret et al.[57] Open label, nonrandom cohort study HCQ group: n = 12; HCQ＋azithromycin group: n = 6; control group: n = 12 HCQ (200 mg/3 times/day for 10 days) HCQ alone or in combination with azithromycin could effectively eliminate nasopharyngeal virus in 3–5 days. Nasopharyngeal virus determination was used as main endpoint. Small sample size; Six patients dropped out due to critical illness or intolerance to the drug; Lack of clinical outcomes; Limited follow-up results.\nGautret et al [58]. Observational study HCQ group: n = 80; no control HCQ, 200 mg/3 times/day for 10 days combined with azithromycin 500 mg on the 1st day, 250 mg/day afterward for 5 days The nasopharynx viral load in most patients received HCQ decreased rapidly. Observation of nasopharynx viral load. Observational study design and no control group; No clinical outcomes were analyzed. Possible confounding factors were not adjusted.\nMagagnoli et al [59]. Retrospective study HCQ group:n = 97HCQ＋azithromycin: n = 113No HCQ group:n = 158 Not specified. The use of HCQ, either with or without azithromycin, didn’t reduce the risk of mechanical ventilation in patients hospitalized with COVID-19; Patients treated with HCQ alone was associated with increased overall mortality. The study data comes from a comprehensive electronic medical record; Strictly defined covariates and outcomes; Using propensity scores adjustment for a large number of relevant confounders to make results more persuasive. Retrospective nature of the study; The subjects included only men and most of them were black; Despite adjustments to many possible confounding factors, there may still be undiscovered factors.\nRosenberg et al[60] Retrospective multicenter cohort study HCQ group:n = 271;HCQ ＋azithromycin group:n = 735control group:n = 221 HCQ:200 mg/400 mg/600 mg/other/unknown, frequency: once a day/twice a day/other/unknownazithromycin:200 mg/250 mg/400 mg/500 mg/other/unknown, methods:Oral/IV/unknown,frequency: only once/once a day/twice a day/other/unknown Treatment with HCQ, azithromycin, or both, compared with neither treatment, was not significantly associated with differences in in-hospital mortality. This study include a large, random sample from 25 metropolitan New York hospitals. The sample was drawnearly in the epidemic to include patients with long, complicated, and ongoing hospital stays; In-hospital mortality was used as primary outcome. Retrospective study design; There may be missing information; Mortality was limited to in-hospital death; There may be potential confounders. The dosing in the doses and frequencies of HCQ and azithromycin varied greatly. The confidence intervals for some of the findings are wide.\nMehraet al[61] Multinational real-world analysis Teatment groups: n = 14,888Control group: n = 81,144 Mean daily dose: CQ 765 mg, (SD 308); HCQ 596 mg(126); CQ with a macrolide 790 mg(320); HCQ with a macrolide 597 mg(128).mean duration:CQ 6.6 days(2.4); HCQ 4.2 days(1.9);CQ with a macrolide 6.8 days(2.5); HCQ with a macrolide 4.3 days (2.0) A benefit of HCQ or CQ, when used alone or witha macrolide, on in-hospital outcomes for COVID-19 was not observed. Large multinational real-world data and large number of study populations. There may be potential confounders; It did not measure QT intervals and stratify the arrhythmia pattern; It did not determine whether the increased risk of death in-hospital and use of drug treatment regimens were directly related to cardiovascular risk; It did not observe the risk of the drug dose-response analysis.\nSeveral trials evaluated the efficacy of HCQ for the treatment of COVID-19 (Table 1). In a randomized clinical trial from Wuhan about HCQ treatment of mild COVID-19 [50], 31 out of 62 patients received HCQ (200 mg/2 times/day for 5 days). The results showed that the temperature recovery time in the HCQ group was improved compared with the control group (average days, 2.2 vs. 3.2); the cough relief time was shorter in the HCQ group than the control group (average days, 2.4 vs. 3.1); and the improvement rate of pneumonia in the HCQ group was higher than the control group (80.6% vs. 54.8%). However, only 48% of patients (15/31) in HCQ group and 71% of patients (22/31) in control group had cough at baseline and the duration of cough was not described. Improvement of symptoms were small and the trial was terminated prematurely. These factors and the low sample size compromise the reliability of the results of this study. Importantly, evaluation of HCQ in the COVID-19 pandemic areas have shown that HCQ can help patients with mild symptoms, and may potentially reduce transmission in areas lacking isolation facilities [51,52]. However, in areas with strict isolation standards, the use of HCQ to reduce transmission or for treatment of mild COVID-19 cases may not be beneficial in risk-benefit analysis [51,52]. Nevertheless, there is an urgent need for drugs and therapeutics in severe cases, which require randomized controlled trials. A study from four French tertiary care centers included 181 patients hospitalized for COVID-19 and requiring oxygen (2 L/min): 84 patients received HCQ (600 mg/day) within 48 hours of admission (HCQ group) and 97 did not (no-HCQ group) [53]. The results showed that the patients transferred to the ICU or died within 7 days and developed ARDS within 7 days had no significant differences between the HCQ group and no-HCQ group. Eight patients in the HCQ group (9.5%) discontinued HCQ due to electrocardiogram alterations. These results do not support the use of HCQ for treating hospitalized COVID-19-related hypoxic pneumonia patients. It is worth noting that in the study’s propensity score model, four possible important prognostic variables were unbalanced and a center effect was not considered, which all can cause bias for study results. In a multicenter, randomized, parallel trial about HCQ in patients with mainly mild to moderate COVID-19 [54], 80 patients received ‘standard care’ and 70 patients received HCQ (1200 mg daily for 3 days, and then 800 mg daily for 2 weeks [mild to moderate disease] or 3 weeks [severe disease]). The results showed that the 28-days negative conversion probability in ‘standard care’＋HCQ group was 85.4%, similar to the ‘standard care’ group (81.2%). HCQ did not show additional benefits of viral elimination in patients with mild to moderate COVID-19. However, the study could not evaluate the antiviral effect of HCQ at early stages of disease, which is a critical period of antiviral treatment. In addition, viral RNA specimens were mostly from the upper respiratory tract rather than bronchoalveolar lavage fluid, which may cause false negative results. Due to the small number of severe patients, this study could not provide evidence regarding the effect of HCQ on the disease progression or regression. In another large observational study involving 1376 cases of COVID-19 from New York, 811 patients received HCQ (600 mg/2 times on the first day, then 400 mg once a day for 4 days) within 24 or 48 hours of admission and 565 did not [55]. This study found no correlation between HCQ use and significantly higher or lower risk of intubation or death. However, in this study, even after the propensity score-matching, the diseases in patients receiving HCQ were more severe at baseline than those in the patients not receiving. Notably, according to another recent study [56], low dose of HCQ reduced fatality of critically ill patients with COVID-19 without apparent toxicity. This retrospective study included 550 patients who need mechanical ventilation, of which 48 received HCQ treatment (200 mg/2 times/day for 7 to 10 days) and 502 did not. The fatalities of the HCQ group was significantly lower than no-HCQ group (18.8% vs 47.4%, P \u003c 0.05), and the inflammatory cytokine IL-6 in the HCQ group decreased significantly from 22.2 (8.3 to 118.9 pg/mL) at the beginning of treatment to 5.2 (3.0 to 23.4 pg/mL) at the end of treatment. The authors deemed that the anti-inflammatory effect of low-dose HCQ and the activity of inhibiting viral replication may have important significance in critically ill patients with COVID-19. Yet, this study is flawed due to its retrospective nature and the small number of HCQ treated patients included. In short, some initial studies have shown that HCQ appears to have a curative effect on patients with mild COVID-19, but subsequent studies indicate that HCQ had no significant benefit in COVID-19 patients with viral conversion and the risk of intubation or death. Although some recent studies show that low-dose HCQ could potentially reduce the mortality of severe COVID-19 patients, there are other studies showing that the HCQ use had no effect on risk of intubation or death.\nThere are also several reports that investigated the efficacy of CQ or HCQ in combination with a macrolide in the treatment of COVID-19 (Table 1). In an open nonrandom clinical trial conducted in France [57], of the 36 participants, 20 patients were given HCQ (200 mg/3 times) with 6 receiving added azithromycin, and 16 controls. The results showed that compared with the control group, HCQ alone or in combination with azithromycin could effectively eliminate nasopharyngeal virus in 3–5 days. On the 6th day after treatment, the virus clearance rates of HCQ combined with azithromycin, HCQ alone and controls were 100%, 57.1% and 12.5%, respectively (P \u003c 0.001). This study indicated that the combined application of azithromycin and HCQ appears to have a synergistic effect. However, the trial design and the results were unreliable, as six patients in the HCQ group discontinued treatment early due to critical illness or intolerance to the drugs and were excluded from the analysis. The assessment of efficacy was based on viral load rather than a clinical endpoint. An observational study in 80 COVID-19 patients evaluated the efficacy of HCQ (200 mg/3 times/day for 10 days) in combination with azithromycin (500 mg on the first day, 250 mg/day afterward for 5 days) and showed that all patients’ clinical symptoms were improved, except for one patient aged over 86 years who died due to critical illness [58]. The nasopharynx viral load in most patients decreased rapidly, and the negative rates of viral nucleic acid conversion on days 7 and 8 were about 83% and 93%, respectively. About 97.5% of patients had negative virus culture in respiratory specimens on the fifth day. However, this study had no control group, thus the results were difficult to interpret [58]. Some recent studies have yielded different results about the efficacy of HCQ combined with azithromycin. A retrospective study including 368 patients (97 patients received HCQ, 113 patients received HCQ + azithromycin and 158 patients received no HCQ) from USA [59] showed that the rates of ventilation in the HCQ, HCQ+azithromycin and no HCQ groups had no significant differences. Unfortunately, theHCQ group (but not in the HCQ+azithromycin group) had a higher risk of death from any case than the no HCQ group. This study showed no evidence that the use of HCQ, either with or without azithromycin, reduced the risk of mechanical ventilation in patients hospitalized with COVID-19. Noticeably, in patients treated with HCQ alone, an association with increased overall mortality was observed [59]. In this study, the subjects included were only men and most of them were black, which may affect the generality of the results. In addition, the patients who received HCQ or azithromycin were more severe, which may also affect the results. In a retrospective multicenter cohort study of a random sample of COVID-19 patients from 25 hospitals in New York [60], totaling 1438 patients, 735 received HCQ and azithromycin, 271 received HCQ alone, 211 received azithromycin alone and 221 received neither drug (HCQ or azithromycin). The results showed that the hospital mortality rate of patients receiving HCQ＋azithromycin was 25.7%, HCQ alone was 19.9%, azithromycin alone was 10.0% and neither drug was 12.7%. In adjusted Cox proportional hazards models, compared with patients receiving neither drug, there were no significant differences in hospital mortality rate for patients receiving HC＋azithromycin, HCQ alone, or azithromycin alone. In this study, the sample size is large and includes patients with long-term, complex and ongoing hospitalization. However, the mortality rate of this study was limited to in-hospital deaths, and patients discharged during the study period were considered alive, which may underestimate the morality rate. Recently, a multinational registry analysis about HCQ or CQ with or without second-generation macrolides (especial azithromycin and clarithromycin) for treatment of COVID-19 was reported [61]. A total of 96,032 patients were included in this study. Of these, 1868 received CQ, 3783 received CQ with a macrolide, 3016 received HCQ and 6221 received HCQ with a macrolide and 8114 patients as control group. After controlling various confounding factors related to disease, when compared with the mortality in the control group (9.3%), CQ group was 16.4%, CQ with a macrolide group was 22.2%, HCQ group was 18.0% and HCQ group with a macrolide was 23.8%; each group was associated with an increased risk of hospital mortality independently. Apart from this, compared with the control group (0.3%), CQ group (4.3%), CQ with a macrolide group (6.5%), HCQ group (6.1%) and HCQ with a macrolide group (8.1%) were independently associated with a risk for ventricular arrhythmia during hospitalization [61]. This study showed that CQ or HCQ (used alone or combination with a macrolide) was associated with an increased hazard for in-hospital death and an increased risk of ventricular arrhythmias. This study included a large number of patients, but it is not a randomized clinical trial. In short, some small studies have shown that HCQ combined with azithromycin could quickly and effectively eliminate viruses, but the design of these studies was flawed in many aspects, making the results unconvincing. Several subsequent studies have shown that the combination of HCQ or CQ and macrolides (azithromycin or clarithromycin) has no obvious correlation with a reduced risk for mechanical ventilation, and may even increase the risk of arrhythmia and in-hospital mortality.\nIn summary, although CQ/HCQ appeared to exhibit a favorable effect on COVID-19 patients in some initial studies of small numbers of patients, the most recent studies with larger sample sizes revealed that CQ/HCQ exhibited no significant improvement of disease but even an increased overall mortality in COVID-19 patients. The studies on the combination of HCQ or CQ and macrolides (azithromycin or clarithromycin) also showed conflicting findings. Therefore, caution should be taken regarding the use of CQ/HCQ treatment in COVID-19 due to the uncertainty of efficacy, the potential adverse effects and the various defects in the studies. According to the Chinese Clinical Trial Registry (ChiCTR) (http://www.chictr.org.cn/index.aspx) and the International Clinical Trials Registry Platform (ICTRP) (https://www.who.int/ictrp/en/), currently, there are more than 200 ongoing clinical trials for CQ/HCQ. Current findings suggest that CQ/HCQ alone or in combination with macrolides should not be recommended for widespread use in COVID-19 (except in clinical trials). Results from these ongoing prospective, randomized, controlled studies are required before these drugs are recommended for the treatment of COVID-19."}

LitCovid-PD-GO-BP

{"project":"LitCovid-PD-GO-BP","denotations":[{"id":"T60","span":{"begin":13338,"end":13366},"obj":"http://purl.obolibrary.org/obo/GO_1903901"},{"id":"T61","span":{"begin":13349,"end":13366},"obj":"http://purl.obolibrary.org/obo/GO_0019079"},{"id":"T62","span":{"begin":13349,"end":13366},"obj":"http://purl.obolibrary.org/obo/GO_0019058"}],"text":"5. Clinical efficacy of CQ/HCQ in the treatment of COVID-19\nOnly two published clinical reports have studied the efficacy of CQ in COVID-19 patients (Table 1). One study used CQ to treat more than 100 patients with COVID-19 and claimed that CQ was superior to the control group in suppressing the deterioration of pneumonia, improving lung imaging, promoting viral conversion and shortening the course of disease. Serious adverse effects were not observed in these patients [48]. However, this report did not provide any details about the study design and patient data, thus it is difficult to evaluate the validity. Recently, a parallel, double-blind, randomized, phase IIB clinical trial was performed in Brazil [49]. In this study, 81 severe COVID-19 patients were randomly divided into two groups: 41 patients received high-dose CQ (600 mg/2 times/day for 10 day) and 40 patients received low-dose CQ (450 mg/2 times on day 1 and then 450 mg/1 time/day for 4 days). The 13-day mortality rate in the high-dose group was more than double that in low-dose group (39.0% vs. 16.0%). The high-dosage group exhibited more instance of corrected QT (QTc) interval prolongation (\u003e500 milliseconds (ms); 7 of 37 [18.9%]) than the low-dosage group (4 of 36 [11.1%]). These findings suggest that the higher CQ dosage should not be recommended for critically ill patients with COVID-19 [49].\nTable 1. Outcomes and advantage/limitation of chloroquine (CQ)/hydroxychloroquine (HCQ) clinical studies for COVID-19.\nAuthor (Reference) Study design Patients Treatment Outcomes Advantage Limitations\nGao et al [48]. Rough and simple description Not mentioned CQ (No specific dosage was mentioned) CQ was superior to control in suppressing pneumonia deterioration, improving lung imaging, promoting viral conversion and shortening disease course. Not significant. No study design and the specific number of patients and controls were provided and thus the result appears to be unconvincing.\nBorba et al [49]. Randomized controlled trial High-dose CQ group: n = 40;Low-dose CQ group:n = 41 high-dose CQ (600 mg/2 times/day, for 10 day);low-dose CQ (450 mg/2 times/day for 5 days, double dose on 1st day) The mortality rate in the high-dose group was more than double that in low-dose group Double-blind study; 2 dosages of CQ for the first time in severe COVID-19 Small sample size; single-center design; Lack of a placebo control; Lack of exclusion criteria based on the QTc interval at baseline\nChen et al.[50] Randomized trial HCQ group: n = 31; control group: n = 30 HCQ (200 mg/2 times/day for 5 days) HCQ group have small improvement in body temperature and cough compered with control group Randomized trial. Small sample size; Single-center design; Small improvement in temperature and cough.\nMahévas et al [53]. Comparative study HCQ group: n = 84; control group: n = 97 HCQ 600 mg/day for 7 days Compared with control group, a reduction of admissions to ICU or death 7 days after hospital admission was not observed in HCQ group. Relatively larger sample size in HCQ treatment and control groups. Nonrandomized design; In propensity score model, four possible important prognostic variables were unbalanced.\nTang et al [54]. Open label, randomized controlled trial HCQ group: n = 70; control group: n = 80. HCQ 1200 mg daily for 3 days, 800 mg daily for 2 weeks (mild to moderate disease)/3 weeks(severe disease) HCQ did not show additional benefits of vial elimination in patients with mild to moderate COVID-19. Randomized controlled study. Lack of a placebo control group; Design introduces the possibility of biased investigator determined assessment and unbalanced dosage adjustment; Randomization of sequential envelopes may be biased. The antiviral efficacy of HCQ was not assessed at an earlier stage; Most patients are mild to severe, and the effect of HCQ on disease progression or regression could not be provided. The trial terminated early due to the difficulty to recruit enough patients. Some secondary endpoints could not be analyzed by the cutoff date; Viral RNA specimens are mostly from the upper respiratory tract rather than bronchoalveolar lavage fluid, which may cause false negative results.\nGeleris et al [55]. Observational study HCQ group: n = 811; no-HCQ group: n = 565 HCQ (600 mg/2 times on the first day, then 400 mg once a day for 4 days) No correlation between the HCQ use and significant higher or lower risk of intubation or death was observed. Large sample size; Minimization of the unmeasured confusion and error through multivariable Cox model with inverse probability weighting according to the propensity score. Single-center design; missing of some variables; Potential for inaccuracies in the electronic health records.\nYu et al [56]. Retrospective study HCQ group: n = 48; no-HCQ group: n = 502 HCQ (200 mg/2 times/day, for 7 to 10 days) The fatalities of HCQ group was significantly lower than no-HCQ group. HCQ treatment was related to significantly reduced mortality in critically ill COVID-19 patients and greatly lowered IL-6 level. Mortality was used as a measure of outcome and the study included critically ill patients. Retrospective design of the study and the number of HCQ group patients was small.\nGautret et al.[57] Open label, nonrandom cohort study HCQ group: n = 12; HCQ＋azithromycin group: n = 6; control group: n = 12 HCQ (200 mg/3 times/day for 10 days) HCQ alone or in combination with azithromycin could effectively eliminate nasopharyngeal virus in 3–5 days. Nasopharyngeal virus determination was used as main endpoint. Small sample size; Six patients dropped out due to critical illness or intolerance to the drug; Lack of clinical outcomes; Limited follow-up results.\nGautret et al [58]. Observational study HCQ group: n = 80; no control HCQ, 200 mg/3 times/day for 10 days combined with azithromycin 500 mg on the 1st day, 250 mg/day afterward for 5 days The nasopharynx viral load in most patients received HCQ decreased rapidly. Observation of nasopharynx viral load. Observational study design and no control group; No clinical outcomes were analyzed. Possible confounding factors were not adjusted.\nMagagnoli et al [59]. Retrospective study HCQ group:n = 97HCQ＋azithromycin: n = 113No HCQ group:n = 158 Not specified. The use of HCQ, either with or without azithromycin, didn’t reduce the risk of mechanical ventilation in patients hospitalized with COVID-19; Patients treated with HCQ alone was associated with increased overall mortality. The study data comes from a comprehensive electronic medical record; Strictly defined covariates and outcomes; Using propensity scores adjustment for a large number of relevant confounders to make results more persuasive. Retrospective nature of the study; The subjects included only men and most of them were black; Despite adjustments to many possible confounding factors, there may still be undiscovered factors.\nRosenberg et al[60] Retrospective multicenter cohort study HCQ group:n = 271;HCQ ＋azithromycin group:n = 735control group:n = 221 HCQ:200 mg/400 mg/600 mg/other/unknown, frequency: once a day/twice a day/other/unknownazithromycin:200 mg/250 mg/400 mg/500 mg/other/unknown, methods:Oral/IV/unknown,frequency: only once/once a day/twice a day/other/unknown Treatment with HCQ, azithromycin, or both, compared with neither treatment, was not significantly associated with differences in in-hospital mortality. This study include a large, random sample from 25 metropolitan New York hospitals. The sample was drawnearly in the epidemic to include patients with long, complicated, and ongoing hospital stays; In-hospital mortality was used as primary outcome. Retrospective study design; There may be missing information; Mortality was limited to in-hospital death; There may be potential confounders. The dosing in the doses and frequencies of HCQ and azithromycin varied greatly. The confidence intervals for some of the findings are wide.\nMehraet al[61] Multinational real-world analysis Teatment groups: n = 14,888Control group: n = 81,144 Mean daily dose: CQ 765 mg, (SD 308); HCQ 596 mg(126); CQ with a macrolide 790 mg(320); HCQ with a macrolide 597 mg(128).mean duration:CQ 6.6 days(2.4); HCQ 4.2 days(1.9);CQ with a macrolide 6.8 days(2.5); HCQ with a macrolide 4.3 days (2.0) A benefit of HCQ or CQ, when used alone or witha macrolide, on in-hospital outcomes for COVID-19 was not observed. Large multinational real-world data and large number of study populations. There may be potential confounders; It did not measure QT intervals and stratify the arrhythmia pattern; It did not determine whether the increased risk of death in-hospital and use of drug treatment regimens were directly related to cardiovascular risk; It did not observe the risk of the drug dose-response analysis.\nSeveral trials evaluated the efficacy of HCQ for the treatment of COVID-19 (Table 1). In a randomized clinical trial from Wuhan about HCQ treatment of mild COVID-19 [50], 31 out of 62 patients received HCQ (200 mg/2 times/day for 5 days). The results showed that the temperature recovery time in the HCQ group was improved compared with the control group (average days, 2.2 vs. 3.2); the cough relief time was shorter in the HCQ group than the control group (average days, 2.4 vs. 3.1); and the improvement rate of pneumonia in the HCQ group was higher than the control group (80.6% vs. 54.8%). However, only 48% of patients (15/31) in HCQ group and 71% of patients (22/31) in control group had cough at baseline and the duration of cough was not described. Improvement of symptoms were small and the trial was terminated prematurely. These factors and the low sample size compromise the reliability of the results of this study. Importantly, evaluation of HCQ in the COVID-19 pandemic areas have shown that HCQ can help patients with mild symptoms, and may potentially reduce transmission in areas lacking isolation facilities [51,52]. However, in areas with strict isolation standards, the use of HCQ to reduce transmission or for treatment of mild COVID-19 cases may not be beneficial in risk-benefit analysis [51,52]. Nevertheless, there is an urgent need for drugs and therapeutics in severe cases, which require randomized controlled trials. A study from four French tertiary care centers included 181 patients hospitalized for COVID-19 and requiring oxygen (2 L/min): 84 patients received HCQ (600 mg/day) within 48 hours of admission (HCQ group) and 97 did not (no-HCQ group) [53]. The results showed that the patients transferred to the ICU or died within 7 days and developed ARDS within 7 days had no significant differences between the HCQ group and no-HCQ group. Eight patients in the HCQ group (9.5%) discontinued HCQ due to electrocardiogram alterations. These results do not support the use of HCQ for treating hospitalized COVID-19-related hypoxic pneumonia patients. It is worth noting that in the study’s propensity score model, four possible important prognostic variables were unbalanced and a center effect was not considered, which all can cause bias for study results. In a multicenter, randomized, parallel trial about HCQ in patients with mainly mild to moderate COVID-19 [54], 80 patients received ‘standard care’ and 70 patients received HCQ (1200 mg daily for 3 days, and then 800 mg daily for 2 weeks [mild to moderate disease] or 3 weeks [severe disease]). The results showed that the 28-days negative conversion probability in ‘standard care’＋HCQ group was 85.4%, similar to the ‘standard care’ group (81.2%). HCQ did not show additional benefits of viral elimination in patients with mild to moderate COVID-19. However, the study could not evaluate the antiviral effect of HCQ at early stages of disease, which is a critical period of antiviral treatment. In addition, viral RNA specimens were mostly from the upper respiratory tract rather than bronchoalveolar lavage fluid, which may cause false negative results. Due to the small number of severe patients, this study could not provide evidence regarding the effect of HCQ on the disease progression or regression. In another large observational study involving 1376 cases of COVID-19 from New York, 811 patients received HCQ (600 mg/2 times on the first day, then 400 mg once a day for 4 days) within 24 or 48 hours of admission and 565 did not [55]. This study found no correlation between HCQ use and significantly higher or lower risk of intubation or death. However, in this study, even after the propensity score-matching, the diseases in patients receiving HCQ were more severe at baseline than those in the patients not receiving. Notably, according to another recent study [56], low dose of HCQ reduced fatality of critically ill patients with COVID-19 without apparent toxicity. This retrospective study included 550 patients who need mechanical ventilation, of which 48 received HCQ treatment (200 mg/2 times/day for 7 to 10 days) and 502 did not. The fatalities of the HCQ group was significantly lower than no-HCQ group (18.8% vs 47.4%, P \u003c 0.05), and the inflammatory cytokine IL-6 in the HCQ group decreased significantly from 22.2 (8.3 to 118.9 pg/mL) at the beginning of treatment to 5.2 (3.0 to 23.4 pg/mL) at the end of treatment. The authors deemed that the anti-inflammatory effect of low-dose HCQ and the activity of inhibiting viral replication may have important significance in critically ill patients with COVID-19. Yet, this study is flawed due to its retrospective nature and the small number of HCQ treated patients included. In short, some initial studies have shown that HCQ appears to have a curative effect on patients with mild COVID-19, but subsequent studies indicate that HCQ had no significant benefit in COVID-19 patients with viral conversion and the risk of intubation or death. Although some recent studies show that low-dose HCQ could potentially reduce the mortality of severe COVID-19 patients, there are other studies showing that the HCQ use had no effect on risk of intubation or death.\nThere are also several reports that investigated the efficacy of CQ or HCQ in combination with a macrolide in the treatment of COVID-19 (Table 1). In an open nonrandom clinical trial conducted in France [57], of the 36 participants, 20 patients were given HCQ (200 mg/3 times) with 6 receiving added azithromycin, and 16 controls. The results showed that compared with the control group, HCQ alone or in combination with azithromycin could effectively eliminate nasopharyngeal virus in 3–5 days. On the 6th day after treatment, the virus clearance rates of HCQ combined with azithromycin, HCQ alone and controls were 100%, 57.1% and 12.5%, respectively (P \u003c 0.001). This study indicated that the combined application of azithromycin and HCQ appears to have a synergistic effect. However, the trial design and the results were unreliable, as six patients in the HCQ group discontinued treatment early due to critical illness or intolerance to the drugs and were excluded from the analysis. The assessment of efficacy was based on viral load rather than a clinical endpoint. An observational study in 80 COVID-19 patients evaluated the efficacy of HCQ (200 mg/3 times/day for 10 days) in combination with azithromycin (500 mg on the first day, 250 mg/day afterward for 5 days) and showed that all patients’ clinical symptoms were improved, except for one patient aged over 86 years who died due to critical illness [58]. The nasopharynx viral load in most patients decreased rapidly, and the negative rates of viral nucleic acid conversion on days 7 and 8 were about 83% and 93%, respectively. About 97.5% of patients had negative virus culture in respiratory specimens on the fifth day. However, this study had no control group, thus the results were difficult to interpret [58]. Some recent studies have yielded different results about the efficacy of HCQ combined with azithromycin. A retrospective study including 368 patients (97 patients received HCQ, 113 patients received HCQ + azithromycin and 158 patients received no HCQ) from USA [59] showed that the rates of ventilation in the HCQ, HCQ+azithromycin and no HCQ groups had no significant differences. Unfortunately, theHCQ group (but not in the HCQ+azithromycin group) had a higher risk of death from any case than the no HCQ group. This study showed no evidence that the use of HCQ, either with or without azithromycin, reduced the risk of mechanical ventilation in patients hospitalized with COVID-19. Noticeably, in patients treated with HCQ alone, an association with increased overall mortality was observed [59]. In this study, the subjects included were only men and most of them were black, which may affect the generality of the results. In addition, the patients who received HCQ or azithromycin were more severe, which may also affect the results. In a retrospective multicenter cohort study of a random sample of COVID-19 patients from 25 hospitals in New York [60], totaling 1438 patients, 735 received HCQ and azithromycin, 271 received HCQ alone, 211 received azithromycin alone and 221 received neither drug (HCQ or azithromycin). The results showed that the hospital mortality rate of patients receiving HCQ＋azithromycin was 25.7%, HCQ alone was 19.9%, azithromycin alone was 10.0% and neither drug was 12.7%. In adjusted Cox proportional hazards models, compared with patients receiving neither drug, there were no significant differences in hospital mortality rate for patients receiving HC＋azithromycin, HCQ alone, or azithromycin alone. In this study, the sample size is large and includes patients with long-term, complex and ongoing hospitalization. However, the mortality rate of this study was limited to in-hospital deaths, and patients discharged during the study period were considered alive, which may underestimate the morality rate. Recently, a multinational registry analysis about HCQ or CQ with or without second-generation macrolides (especial azithromycin and clarithromycin) for treatment of COVID-19 was reported [61]. A total of 96,032 patients were included in this study. Of these, 1868 received CQ, 3783 received CQ with a macrolide, 3016 received HCQ and 6221 received HCQ with a macrolide and 8114 patients as control group. After controlling various confounding factors related to disease, when compared with the mortality in the control group (9.3%), CQ group was 16.4%, CQ with a macrolide group was 22.2%, HCQ group was 18.0% and HCQ group with a macrolide was 23.8%; each group was associated with an increased risk of hospital mortality independently. Apart from this, compared with the control group (0.3%), CQ group (4.3%), CQ with a macrolide group (6.5%), HCQ group (6.1%) and HCQ with a macrolide group (8.1%) were independently associated with a risk for ventricular arrhythmia during hospitalization [61]. This study showed that CQ or HCQ (used alone or combination with a macrolide) was associated with an increased hazard for in-hospital death and an increased risk of ventricular arrhythmias. This study included a large number of patients, but it is not a randomized clinical trial. In short, some small studies have shown that HCQ combined with azithromycin could quickly and effectively eliminate viruses, but the design of these studies was flawed in many aspects, making the results unconvincing. Several subsequent studies have shown that the combination of HCQ or CQ and macrolides (azithromycin or clarithromycin) has no obvious correlation with a reduced risk for mechanical ventilation, and may even increase the risk of arrhythmia and in-hospital mortality.\nIn summary, although CQ/HCQ appeared to exhibit a favorable effect on COVID-19 patients in some initial studies of small numbers of patients, the most recent studies with larger sample sizes revealed that CQ/HCQ exhibited no significant improvement of disease but even an increased overall mortality in COVID-19 patients. The studies on the combination of HCQ or CQ and macrolides (azithromycin or clarithromycin) also showed conflicting findings. Therefore, caution should be taken regarding the use of CQ/HCQ treatment in COVID-19 due to the uncertainty of efficacy, the potential adverse effects and the various defects in the studies. According to the Chinese Clinical Trial Registry (ChiCTR) (http://www.chictr.org.cn/index.aspx) and the International Clinical Trials Registry Platform (ICTRP) (https://www.who.int/ictrp/en/), currently, there are more than 200 ongoing clinical trials for CQ/HCQ. Current findings suggest that CQ/HCQ alone or in combination with macrolides should not be recommended for widespread use in COVID-19 (except in clinical trials). Results from these ongoing prospective, randomized, controlled studies are required before these drugs are recommended for the treatment of COVID-19."}

LitCovid-PubTator

LitCovid-sentences

LitCovid-PD-HP

2_test

{"project":"2_test","denotations":[{"id":"32496926-32074550-132195701","span":{"begin":476,"end":478},"obj":"32074550"},{"id":"32496926-32074550-132195702","span":{"begin":1595,"end":1597},"obj":"32074550"},{"id":"32496926-32409561-132195703","span":{"begin":3212,"end":3214},"obj":"32409561"},{"id":"32496926-32409561-132195704","span":{"begin":11212,"end":11214},"obj":"32409561"}],"text":"5. Clinical efficacy of CQ/HCQ in the treatment of COVID-19\nOnly two published clinical reports have studied the efficacy of CQ in COVID-19 patients (Table 1). One study used CQ to treat more than 100 patients with COVID-19 and claimed that CQ was superior to the control group in suppressing the deterioration of pneumonia, improving lung imaging, promoting viral conversion and shortening the course of disease. Serious adverse effects were not observed in these patients [48]. However, this report did not provide any details about the study design and patient data, thus it is difficult to evaluate the validity. Recently, a parallel, double-blind, randomized, phase IIB clinical trial was performed in Brazil [49]. In this study, 81 severe COVID-19 patients were randomly divided into two groups: 41 patients received high-dose CQ (600 mg/2 times/day for 10 day) and 40 patients received low-dose CQ (450 mg/2 times on day 1 and then 450 mg/1 time/day for 4 days). The 13-day mortality rate in the high-dose group was more than double that in low-dose group (39.0% vs. 16.0%). The high-dosage group exhibited more instance of corrected QT (QTc) interval prolongation (\u003e500 milliseconds (ms); 7 of 37 [18.9%]) than the low-dosage group (4 of 36 [11.1%]). These findings suggest that the higher CQ dosage should not be recommended for critically ill patients with COVID-19 [49].\nTable 1. Outcomes and advantage/limitation of chloroquine (CQ)/hydroxychloroquine (HCQ) clinical studies for COVID-19.\nAuthor (Reference) Study design Patients Treatment Outcomes Advantage Limitations\nGao et al [48]. Rough and simple description Not mentioned CQ (No specific dosage was mentioned) CQ was superior to control in suppressing pneumonia deterioration, improving lung imaging, promoting viral conversion and shortening disease course. Not significant. No study design and the specific number of patients and controls were provided and thus the result appears to be unconvincing.\nBorba et al [49]. Randomized controlled trial High-dose CQ group: n = 40;Low-dose CQ group:n = 41 high-dose CQ (600 mg/2 times/day, for 10 day);low-dose CQ (450 mg/2 times/day for 5 days, double dose on 1st day) The mortality rate in the high-dose group was more than double that in low-dose group Double-blind study; 2 dosages of CQ for the first time in severe COVID-19 Small sample size; single-center design; Lack of a placebo control; Lack of exclusion criteria based on the QTc interval at baseline\nChen et al.[50] Randomized trial HCQ group: n = 31; control group: n = 30 HCQ (200 mg/2 times/day for 5 days) HCQ group have small improvement in body temperature and cough compered with control group Randomized trial. Small sample size; Single-center design; Small improvement in temperature and cough.\nMahévas et al [53]. Comparative study HCQ group: n = 84; control group: n = 97 HCQ 600 mg/day for 7 days Compared with control group, a reduction of admissions to ICU or death 7 days after hospital admission was not observed in HCQ group. Relatively larger sample size in HCQ treatment and control groups. Nonrandomized design; In propensity score model, four possible important prognostic variables were unbalanced.\nTang et al [54]. Open label, randomized controlled trial HCQ group: n = 70; control group: n = 80. HCQ 1200 mg daily for 3 days, 800 mg daily for 2 weeks (mild to moderate disease)/3 weeks(severe disease) HCQ did not show additional benefits of vial elimination in patients with mild to moderate COVID-19. Randomized controlled study. Lack of a placebo control group; Design introduces the possibility of biased investigator determined assessment and unbalanced dosage adjustment; Randomization of sequential envelopes may be biased. The antiviral efficacy of HCQ was not assessed at an earlier stage; Most patients are mild to severe, and the effect of HCQ on disease progression or regression could not be provided. The trial terminated early due to the difficulty to recruit enough patients. Some secondary endpoints could not be analyzed by the cutoff date; Viral RNA specimens are mostly from the upper respiratory tract rather than bronchoalveolar lavage fluid, which may cause false negative results.\nGeleris et al [55]. Observational study HCQ group: n = 811; no-HCQ group: n = 565 HCQ (600 mg/2 times on the first day, then 400 mg once a day for 4 days) No correlation between the HCQ use and significant higher or lower risk of intubation or death was observed. Large sample size; Minimization of the unmeasured confusion and error through multivariable Cox model with inverse probability weighting according to the propensity score. Single-center design; missing of some variables; Potential for inaccuracies in the electronic health records.\nYu et al [56]. Retrospective study HCQ group: n = 48; no-HCQ group: n = 502 HCQ (200 mg/2 times/day, for 7 to 10 days) The fatalities of HCQ group was significantly lower than no-HCQ group. HCQ treatment was related to significantly reduced mortality in critically ill COVID-19 patients and greatly lowered IL-6 level. Mortality was used as a measure of outcome and the study included critically ill patients. Retrospective design of the study and the number of HCQ group patients was small.\nGautret et al.[57] Open label, nonrandom cohort study HCQ group: n = 12; HCQ＋azithromycin group: n = 6; control group: n = 12 HCQ (200 mg/3 times/day for 10 days) HCQ alone or in combination with azithromycin could effectively eliminate nasopharyngeal virus in 3–5 days. Nasopharyngeal virus determination was used as main endpoint. Small sample size; Six patients dropped out due to critical illness or intolerance to the drug; Lack of clinical outcomes; Limited follow-up results.\nGautret et al [58]. Observational study HCQ group: n = 80; no control HCQ, 200 mg/3 times/day for 10 days combined with azithromycin 500 mg on the 1st day, 250 mg/day afterward for 5 days The nasopharynx viral load in most patients received HCQ decreased rapidly. Observation of nasopharynx viral load. Observational study design and no control group; No clinical outcomes were analyzed. Possible confounding factors were not adjusted.\nMagagnoli et al [59]. Retrospective study HCQ group:n = 97HCQ＋azithromycin: n = 113No HCQ group:n = 158 Not specified. The use of HCQ, either with or without azithromycin, didn’t reduce the risk of mechanical ventilation in patients hospitalized with COVID-19; Patients treated with HCQ alone was associated with increased overall mortality. The study data comes from a comprehensive electronic medical record; Strictly defined covariates and outcomes; Using propensity scores adjustment for a large number of relevant confounders to make results more persuasive. Retrospective nature of the study; The subjects included only men and most of them were black; Despite adjustments to many possible confounding factors, there may still be undiscovered factors.\nRosenberg et al[60] Retrospective multicenter cohort study HCQ group:n = 271;HCQ ＋azithromycin group:n = 735control group:n = 221 HCQ:200 mg/400 mg/600 mg/other/unknown, frequency: once a day/twice a day/other/unknownazithromycin:200 mg/250 mg/400 mg/500 mg/other/unknown, methods:Oral/IV/unknown,frequency: only once/once a day/twice a day/other/unknown Treatment with HCQ, azithromycin, or both, compared with neither treatment, was not significantly associated with differences in in-hospital mortality. This study include a large, random sample from 25 metropolitan New York hospitals. The sample was drawnearly in the epidemic to include patients with long, complicated, and ongoing hospital stays; In-hospital mortality was used as primary outcome. Retrospective study design; There may be missing information; Mortality was limited to in-hospital death; There may be potential confounders. The dosing in the doses and frequencies of HCQ and azithromycin varied greatly. The confidence intervals for some of the findings are wide.\nMehraet al[61] Multinational real-world analysis Teatment groups: n = 14,888Control group: n = 81,144 Mean daily dose: CQ 765 mg, (SD 308); HCQ 596 mg(126); CQ with a macrolide 790 mg(320); HCQ with a macrolide 597 mg(128).mean duration:CQ 6.6 days(2.4); HCQ 4.2 days(1.9);CQ with a macrolide 6.8 days(2.5); HCQ with a macrolide 4.3 days (2.0) A benefit of HCQ or CQ, when used alone or witha macrolide, on in-hospital outcomes for COVID-19 was not observed. Large multinational real-world data and large number of study populations. There may be potential confounders; It did not measure QT intervals and stratify the arrhythmia pattern; It did not determine whether the increased risk of death in-hospital and use of drug treatment regimens were directly related to cardiovascular risk; It did not observe the risk of the drug dose-response analysis.\nSeveral trials evaluated the efficacy of HCQ for the treatment of COVID-19 (Table 1). In a randomized clinical trial from Wuhan about HCQ treatment of mild COVID-19 [50], 31 out of 62 patients received HCQ (200 mg/2 times/day for 5 days). The results showed that the temperature recovery time in the HCQ group was improved compared with the control group (average days, 2.2 vs. 3.2); the cough relief time was shorter in the HCQ group than the control group (average days, 2.4 vs. 3.1); and the improvement rate of pneumonia in the HCQ group was higher than the control group (80.6% vs. 54.8%). However, only 48% of patients (15/31) in HCQ group and 71% of patients (22/31) in control group had cough at baseline and the duration of cough was not described. Improvement of symptoms were small and the trial was terminated prematurely. These factors and the low sample size compromise the reliability of the results of this study. Importantly, evaluation of HCQ in the COVID-19 pandemic areas have shown that HCQ can help patients with mild symptoms, and may potentially reduce transmission in areas lacking isolation facilities [51,52]. However, in areas with strict isolation standards, the use of HCQ to reduce transmission or for treatment of mild COVID-19 cases may not be beneficial in risk-benefit analysis [51,52]. Nevertheless, there is an urgent need for drugs and therapeutics in severe cases, which require randomized controlled trials. A study from four French tertiary care centers included 181 patients hospitalized for COVID-19 and requiring oxygen (2 L/min): 84 patients received HCQ (600 mg/day) within 48 hours of admission (HCQ group) and 97 did not (no-HCQ group) [53]. The results showed that the patients transferred to the ICU or died within 7 days and developed ARDS within 7 days had no significant differences between the HCQ group and no-HCQ group. Eight patients in the HCQ group (9.5%) discontinued HCQ due to electrocardiogram alterations. These results do not support the use of HCQ for treating hospitalized COVID-19-related hypoxic pneumonia patients. It is worth noting that in the study’s propensity score model, four possible important prognostic variables were unbalanced and a center effect was not considered, which all can cause bias for study results. In a multicenter, randomized, parallel trial about HCQ in patients with mainly mild to moderate COVID-19 [54], 80 patients received ‘standard care’ and 70 patients received HCQ (1200 mg daily for 3 days, and then 800 mg daily for 2 weeks [mild to moderate disease] or 3 weeks [severe disease]). The results showed that the 28-days negative conversion probability in ‘standard care’＋HCQ group was 85.4%, similar to the ‘standard care’ group (81.2%). HCQ did not show additional benefits of viral elimination in patients with mild to moderate COVID-19. However, the study could not evaluate the antiviral effect of HCQ at early stages of disease, which is a critical period of antiviral treatment. In addition, viral RNA specimens were mostly from the upper respiratory tract rather than bronchoalveolar lavage fluid, which may cause false negative results. Due to the small number of severe patients, this study could not provide evidence regarding the effect of HCQ on the disease progression or regression. In another large observational study involving 1376 cases of COVID-19 from New York, 811 patients received HCQ (600 mg/2 times on the first day, then 400 mg once a day for 4 days) within 24 or 48 hours of admission and 565 did not [55]. This study found no correlation between HCQ use and significantly higher or lower risk of intubation or death. However, in this study, even after the propensity score-matching, the diseases in patients receiving HCQ were more severe at baseline than those in the patients not receiving. Notably, according to another recent study [56], low dose of HCQ reduced fatality of critically ill patients with COVID-19 without apparent toxicity. This retrospective study included 550 patients who need mechanical ventilation, of which 48 received HCQ treatment (200 mg/2 times/day for 7 to 10 days) and 502 did not. The fatalities of the HCQ group was significantly lower than no-HCQ group (18.8% vs 47.4%, P \u003c 0.05), and the inflammatory cytokine IL-6 in the HCQ group decreased significantly from 22.2 (8.3 to 118.9 pg/mL) at the beginning of treatment to 5.2 (3.0 to 23.4 pg/mL) at the end of treatment. The authors deemed that the anti-inflammatory effect of low-dose HCQ and the activity of inhibiting viral replication may have important significance in critically ill patients with COVID-19. Yet, this study is flawed due to its retrospective nature and the small number of HCQ treated patients included. In short, some initial studies have shown that HCQ appears to have a curative effect on patients with mild COVID-19, but subsequent studies indicate that HCQ had no significant benefit in COVID-19 patients with viral conversion and the risk of intubation or death. Although some recent studies show that low-dose HCQ could potentially reduce the mortality of severe COVID-19 patients, there are other studies showing that the HCQ use had no effect on risk of intubation or death.\nThere are also several reports that investigated the efficacy of CQ or HCQ in combination with a macrolide in the treatment of COVID-19 (Table 1). In an open nonrandom clinical trial conducted in France [57], of the 36 participants, 20 patients were given HCQ (200 mg/3 times) with 6 receiving added azithromycin, and 16 controls. The results showed that compared with the control group, HCQ alone or in combination with azithromycin could effectively eliminate nasopharyngeal virus in 3–5 days. On the 6th day after treatment, the virus clearance rates of HCQ combined with azithromycin, HCQ alone and controls were 100%, 57.1% and 12.5%, respectively (P \u003c 0.001). This study indicated that the combined application of azithromycin and HCQ appears to have a synergistic effect. However, the trial design and the results were unreliable, as six patients in the HCQ group discontinued treatment early due to critical illness or intolerance to the drugs and were excluded from the analysis. The assessment of efficacy was based on viral load rather than a clinical endpoint. An observational study in 80 COVID-19 patients evaluated the efficacy of HCQ (200 mg/3 times/day for 10 days) in combination with azithromycin (500 mg on the first day, 250 mg/day afterward for 5 days) and showed that all patients’ clinical symptoms were improved, except for one patient aged over 86 years who died due to critical illness [58]. The nasopharynx viral load in most patients decreased rapidly, and the negative rates of viral nucleic acid conversion on days 7 and 8 were about 83% and 93%, respectively. About 97.5% of patients had negative virus culture in respiratory specimens on the fifth day. However, this study had no control group, thus the results were difficult to interpret [58]. Some recent studies have yielded different results about the efficacy of HCQ combined with azithromycin. A retrospective study including 368 patients (97 patients received HCQ, 113 patients received HCQ + azithromycin and 158 patients received no HCQ) from USA [59] showed that the rates of ventilation in the HCQ, HCQ+azithromycin and no HCQ groups had no significant differences. Unfortunately, theHCQ group (but not in the HCQ+azithromycin group) had a higher risk of death from any case than the no HCQ group. This study showed no evidence that the use of HCQ, either with or without azithromycin, reduced the risk of mechanical ventilation in patients hospitalized with COVID-19. Noticeably, in patients treated with HCQ alone, an association with increased overall mortality was observed [59]. In this study, the subjects included were only men and most of them were black, which may affect the generality of the results. In addition, the patients who received HCQ or azithromycin were more severe, which may also affect the results. In a retrospective multicenter cohort study of a random sample of COVID-19 patients from 25 hospitals in New York [60], totaling 1438 patients, 735 received HCQ and azithromycin, 271 received HCQ alone, 211 received azithromycin alone and 221 received neither drug (HCQ or azithromycin). The results showed that the hospital mortality rate of patients receiving HCQ＋azithromycin was 25.7%, HCQ alone was 19.9%, azithromycin alone was 10.0% and neither drug was 12.7%. In adjusted Cox proportional hazards models, compared with patients receiving neither drug, there were no significant differences in hospital mortality rate for patients receiving HC＋azithromycin, HCQ alone, or azithromycin alone. In this study, the sample size is large and includes patients with long-term, complex and ongoing hospitalization. However, the mortality rate of this study was limited to in-hospital deaths, and patients discharged during the study period were considered alive, which may underestimate the morality rate. Recently, a multinational registry analysis about HCQ or CQ with or without second-generation macrolides (especial azithromycin and clarithromycin) for treatment of COVID-19 was reported [61]. A total of 96,032 patients were included in this study. Of these, 1868 received CQ, 3783 received CQ with a macrolide, 3016 received HCQ and 6221 received HCQ with a macrolide and 8114 patients as control group. After controlling various confounding factors related to disease, when compared with the mortality in the control group (9.3%), CQ group was 16.4%, CQ with a macrolide group was 22.2%, HCQ group was 18.0% and HCQ group with a macrolide was 23.8%; each group was associated with an increased risk of hospital mortality independently. Apart from this, compared with the control group (0.3%), CQ group (4.3%), CQ with a macrolide group (6.5%), HCQ group (6.1%) and HCQ with a macrolide group (8.1%) were independently associated with a risk for ventricular arrhythmia during hospitalization [61]. This study showed that CQ or HCQ (used alone or combination with a macrolide) was associated with an increased hazard for in-hospital death and an increased risk of ventricular arrhythmias. This study included a large number of patients, but it is not a randomized clinical trial. In short, some small studies have shown that HCQ combined with azithromycin could quickly and effectively eliminate viruses, but the design of these studies was flawed in many aspects, making the results unconvincing. Several subsequent studies have shown that the combination of HCQ or CQ and macrolides (azithromycin or clarithromycin) has no obvious correlation with a reduced risk for mechanical ventilation, and may even increase the risk of arrhythmia and in-hospital mortality.\nIn summary, although CQ/HCQ appeared to exhibit a favorable effect on COVID-19 patients in some initial studies of small numbers of patients, the most recent studies with larger sample sizes revealed that CQ/HCQ exhibited no significant improvement of disease but even an increased overall mortality in COVID-19 patients. The studies on the combination of HCQ or CQ and macrolides (azithromycin or clarithromycin) also showed conflicting findings. Therefore, caution should be taken regarding the use of CQ/HCQ treatment in COVID-19 due to the uncertainty of efficacy, the potential adverse effects and the various defects in the studies. According to the Chinese Clinical Trial Registry (ChiCTR) (http://www.chictr.org.cn/index.aspx) and the International Clinical Trials Registry Platform (ICTRP) (https://www.who.int/ictrp/en/), currently, there are more than 200 ongoing clinical trials for CQ/HCQ. Current findings suggest that CQ/HCQ alone or in combination with macrolides should not be recommended for widespread use in COVID-19 (except in clinical trials). Results from these ongoing prospective, randomized, controlled studies are required before these drugs are recommended for the treatment of COVID-19."}

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