Table 1. Outcomes and advantage/limitation of chloroquine (CQ)/hydroxychloroquine (HCQ) clinical studies for COVID-19.
Author (Reference) Study design Patients Treatment Outcomes Advantage Limitations
Gao 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.
Borba 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
Chen 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.
Mahévas 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.
Tang 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.
Geleris 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.
Yu 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.
Gautret 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.
Gautret 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.
Magagnoli 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.
Rosenberg 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.
Mehraet 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.