Chloroquine and Hydroxychloroquine for the Prevention and Treatment of COVID-19: A Fiction, Hope or Hype? An Updated Review

Figures & data

Figure 1 Chemical composition of chloroquine and hydroxychloroquine.

Figure 2 The possible mode of action of chloroquine and hydroxychloroquine versus SARS-CoV-2 infection: (1) interference with the terminal glycosylation of cellular receptor angiotensin-converting enzyme 2 (ACE-2) leads to obstructing virus-receptor attachment; (2) increasing the pH of acidic cellular organelles lead to prevention of endocytosis with adverse influences on post-translational modification of recently synthesized viral RNA and virion transport; (3) blocking of viral protein synthesis and virion assembly.

Figure 3 The possible side effects of chloroquine and hydroxychloroquine.

Figure 4 Cautions and contraindications during treatment with chloroquine (CQ) and hydroxychloroquine (HCQ).

Table 1 The Commonest Drug Interactions and Disease Interactions of the Chloroquine (CQ) and Hydroxychloroquine (HCQ) Regimen

	CQ	HCQ
Drug interactions	Hydroxyzine Azithromycin Ciprofloxacin Duloxetine HCQ Levetiracetam Pregabalin Mefloquine Primaquine Albuterol	Amitriptyline Calcium/Vitamin D Duloxetine Leflunomide Albuterol Tramadol
Disease interactions	Oculotoxicity Porphyria Arrhythmias Bone marrow suppression Ototoxicity Seizures Glucose-6-PD deficiency Hepatotoxicity Myasthenia gravis Psoriasis	Oculotoxicity Porphyria Arrhythmias Bone marrow suppression Ototoxicity Seizures Glucose-6-PD deficiency Hepatotoxicity Myasthenia gravis Psoriasis Diabetes Heart disease Renal impairment

Table 2 Characteristics of the in vitro Investigations on SARS-CoV-2 and Clinical Trials Studying the Efficacy of Chloroquine and Hydroxychloroquine in COVID-19 Patients

Reference and Country	Population (n Patients)	Intervention and Comparison Groups	Primary Outcomes
China^Citation28	in vitro study with SARS-CoV-2-infected Vero cells	Infected Vero cells were treated with CQ or HCQ at 0.032, 0.16, 0.80, 4, 20, or 100 μM for 24 or 48 h.	CQ and HCQ decreased viral replication in a concentration-dependent manner. EC50 values for CQ were 23.90 and 5.47 μM at 24 and 48 h, respectively. EC50 values for HCQ were 6.14 and 0.72 μM at 24 and 48 h, respectively.
China^Citation28	in vitro study with Vero cells	Vero cells were pre-treated CQ or HCQ at 0.032, 0.16, 0.80, 4, 20, or 100 μM for two h and were then infected with SARS-CoV-2 and incubated for 24 or 48 h.	HCQ showed a higher in vitro antiviral influence in comparison with CQ. The EC50 values for CQ were greater than 100 and 18.01 μM at 24 and 48 h, respectively. EC50 values for HCQ were 6.25 and 5.85 μM at 24 and 48 h, respectively.
China^Citation3	in vitro study with African green monkey kidney VeroE6 cells	SARS-CoV-2 infected cells at four different multiplicities of infection (MOI) and treated with CQ or HCQ up to 50 μM for 48 h	CC50 values of CQ and HCQ were 273 and 250 μM, respectively, which are not significantly different. At all MOI (0.01, 0.02, 0.2, and 0.8), EC50 for HCQ (4.51, 4.06, 17.31, and 12.96 μM) was higher than that of CQ (2.71, 3.81, 7.14, and 7.36 μM). Statistically, the variations in EC50 values were significant at MOI of 0.01 (P < 0.05) and 0.2 (P < 0.001).
China^Citation27	in vitro study with Vero E6 cells.	Cells were infected with SARS-CoV-2 at MOI of 0.05 in the presence of different concentrations of CQ, penciclovir, ribavirin, nafamostat, nitazoxanide, remdesivir, favipiravir and chloroquine.	EC50, SI index, and CC50 values for CQ were 1.13 μM, >100 μM, and 88.5. These values were higher for for ribavirin (EC50 = 110 μM, CC50> 400 μM, and  SI > 3.65), penciclovir (EC50 = 96.0 μM, CC50 > 400 μM, SI  > 4.17) and favipiravir (EC50 = 61.9 μM, CC50 > 400 μM, SI  > 6.46), nafamostat (EC50 = 22.50 μM, CC50 > 100 μM, SI  > 4.44), and was comparable to nitazoxanide (EC50 = 2.12 μM; CC50 > 35.53 μM; SI > 16.76) and remdesivir (EC50 = 0.77 μM; CC50 > 100 μM; SI  > 129.87) for EC50.
France^Citation22	Age >12 years and positive for SARS-CoV-2. Patients with HCQ or CQ allergy were excluded or had another recognized contraindication to cure with the drug. Pregnant and breastfeeding patients were excluded.	Oral HCQ 200 mg TD × ten days (n=20). Symptomatic treatment and AZT (n = 6; 500 mg/d on day 1 then 250 mg/d for next 4 days) with HCQ. Patients (n=16) who rejected the cure or had relegation criteria, served as controls.	Control patients were younger than HCQ-treated patients (37.3 years vs 51.2 years). At sixth day post-inclusion, 70% of HCQ-cured patients were negative compared with 12.5% in the control group (p= 0.001). At day six post-inclusion, 100% of patients treated with combination of HCQ and AZT were negative compared with 57.1% in patients cured with HCQ only, and 12.5% in the control group (p<0.001).
China^Citation38	Confirmed COVID-19 patients. Thirty patients were randomly grouped into treatment and control groups.	Oral HCQ sulfate 400 mg OD × 5 days (n=15). No HCQ was provided to Patients (n=15).	On day 7, the number of negative samples did not differ (13 (86.7%) cases in the HCQ group versus 14 (93.3%) cases in the control group; P>0.05) The period from hospitalization to negative result of virus nucleic acid did not differ (4±1.9 days in HCQ versus 2±1.4 days in the control group; P>0.05). The time for body temperature normalization was comparable (1±0.2 day I HCQ group versus 1±0.3 days in the control group). Radiological progress was noted on CT images in 7 cases (46.7%) of the control group and 5 cases (33.3%) of the HCQ group, and all patients revealed amelioration in follow-up examinations. Three cases (20%) of the control group and four cases (26.7%) of the HCQ group had abnormal liver function and transient diarrhoea (P>0.05).
South Korea^Citation46	COVID-19 exposed individuals (211 containing 22 careworkers and 189 patients) with negative PCR tests for COVID-19 in a long-term care hospital in Korea. Four patients and one coworker were not finally completed.	COVID-19 exposed individuals were administered HCQ at 400 mg OD x 14 days during the quarantine. No control groups.	At the ending of two weeks of quarantine, all follow-up PCR tests were negative. A sum of 32 individuals (15.6%) mentioned one or more symptoms through post-exposure prophylaxis. The most common symptoms were skin rash (4.3%), loose stool or diarrhoea (9%), bradycardia (0.95%), and gastrointestinal upset (0.95%). Post-exposure prophylaxis was stopped in 5 patients (2.7%) because of the requirement for fasting (1), bradycardia (2), and gastrointestinal upset (2).
Netherlands^Citation55	Patients (n = 95) were aged 18 years or older and suspected of having COVID-19 disease.	CQ was a loading dose of 600 mg followed by 300 mg BD (starting 12 h after the loading dose), for the next four days	CQ treatment in patients with COVID-19 markedly extended the QTc interval by 34–35 ms; 23% of the patients had a QTc interval exceeding 500 ms. Statistically marked influences were detected on QRS interval (mean difference 6 ms), PR interval (mean difference 8 ms), and heart rate (mean difference –10 bpm).
Netherlands^Citation23	A retrospective investigation of 251 patients having COVID-19.	HCQ was orally administrated at 400 mg BD for one day (loading dose) then 200 mg BD for four days. AZT was orally administrated for five days at a dose of 500 mg OD.	The QTc interval extended from a baseline of 439 ± 29 ms to a maximum value of 473 ± 36 ms (P < .001), which happen on day 4.1 ± 2 of treatment. Extreme novel QTc interval extension to >500 ms revealed in 23% of the patients. One patient showed polymorphic ventricular tachycardia.
USA^Citation56	A retrospective investigation of 1376 patients having COVID-19.	HCQ (n = 811) was provided at 600 mg BD on day 1, followed by 400 mg/d for 4 next days. Control group patients were less adversely ill at baseline than those with HCQ-treated patients (n = 565; the ratio of the partial pressure of arterial oxygen to the fraction of inspired oxygen, 223 vs 360).	HCQ use was not accompanied with a markedly lower or higher hazard of death or intubation (hazard ratio, 1.04; 95% CI, 0.82 to 1.32).
USA^Citation57	A retrospective investigation of 368 patients diagnosed with COVID-19.	HCQ (n = 97) alone and HCQ + AZT (n = 113) in combination. In the control group (n = 158), no HCQ was provided.	The hazard of death from any reason was elevated in the HCQ group (adjusted hazard ratio, 2.61; 95% CI, 1.10 to 6.17; P=0.03). The risk of death was similar in the HCQ+AZ group (adjusted hazard ratio, 1.14; 95% CI, 0.56 to 2.32; P=0.72). The hazard of ventilation was comparable in the HCQ group (adjusted hazard ratio, 1.43; 95% CI, 0.53 to 3.79; P=0.48) and the HC+AZ group (adjusted hazard ratio, 0.43; 95% CI, 0.16 to 1.12; P=0.09).
France^Citation58	A retrospective investigation of 181 patients having COVID-19 and requiring oxygen ≥ 2 L/min.	HCQ (n = 84) 600 mg/d for 7 day In control (n = 97), no HCQ was provided.	20.2% of the patients in the HCQ group were died within seven days or moved to the ICU vs 22.1% in the no–HCQ group (16 vs 21 events, the relative hazard of 0.91, 95% CI 0.47-1.80) in the HCQ group. The death of 2.8% of the patients was within seven days vs 4.6% in the no–HCQ group (three vs four events, the relative risk of 0.61, 95% CI 0.13–2.89). 27.4% in the HCQ group versus 24.1% in control group patients developed acute respiratory distress syndrome within seven days (24 vs 23 events, relative risk of 1.14, 95% CI 0.65-2.00). 8 patients receiving HCQ (9.5%) revealed electrocardiogram modifications requesting HCQ stop.
USA^Citation59	A retrospective investigation of 181 patients having COVID-19.	HCQ at 200–600 mg OD/BD (n = 271) alone; HCQ + AZT (n = 735) in combination; AZT 200–500 mg once/OD/BD (n = 211), and no drug (n =221)	The death of patients treating with AZT alone, 21/211 (10.0% (95% CI, 5.9%-14.0%)), HCQ + AZT was 189/735 (25.7% (95% CI, 22.3%-28.9%)), HCQ alone, 54/271 (19.9% (95% CI, 15.2%-24.7%)), and neither drug, 28/221 (12.7% (95% CI, 8.3%–17.1%)). Co marked variations in mortality for patients receiving HCQ + AZT (hazard ratio of 1.35 (95% CI, 0.76–2.40)), HCQ alone (hazard ratio of 1.08 (95% CI, 0.63–1.85)), or AZT alone (hazard ratio of 0.56 (95% CI, 0.26–1.21)) in comparison with patients administrating neither drug. Cardiac arrest was markedly higher in patients receiving HCQ + AZT (adjusted OR, 2.13 (95% CI, 1.12–4.05)), but not HCQ alone (adjusted OR, 1.91 (95% CI, 0.96–3.81)) or AZT alone (adjusted OR, 0.64 (95% CI, 0.27-1.56)) compared with patients receiving neither drug.
China^Citation60	A retrospective investigation of 181 patients having COVID–19 and treated with HCQ.	HCQ 400 mg/d (200 mg BD) for 7–10 days (n = 48). In the control group (n = 520), no HCQ was provided.	Mortalities reduced in HCQ group (18.8% (9/48) versus 45.8% (238/520) in control group (p<0.001)). The time of hospitalization before patient death was 15 (10–21) days for the HCQ group versus 8 (4–14) days for control groups (p<0.05). The level of inflammatory cytokine IL–6 markedly decreased from 22.2 (8.3–118.9) pg/mL to 5.2 (3.0-23.4) pg/ml (p<0.05) in the HCQ group, but there is no alteration in the control group.
Recovery trial UK^Citation61	An ongoing randomized controlled trial of more than 11,000 COVID-19 patients to date	HCQ(200 mg tablet containing 155 mg base equivalent) received a loading dose of four tablets (800 mg) at zero and six hours, then two tablets (400 mg) starting at twelve hours after the initial dose and then every twelve hours for the next nine days or until discharge.	28-day mortality was 26.8% and 25% in the HCQ and standard of care groups. HCQ treatment was markedly accompanied with an elevated length of hospital stay and elevated hazard of developing to death.
Solidarity trial^Citation54	An ongoing randomized controlled trial of more than 5,000 COVID-19 patients to date	HCQ Standard of care	Not Available; Details were not published.
US and Canada^Citation62	An internet-based randomized controlled trial in non-hospitalized patients in the US and Canada	HCQ(800 mg once, followed by 600 mg in 6 to 8 hours, then 600 mg daily for 4 more days) Placebo	Symptom severity did not significantly differ over 14 days (−0.27 points (95% CI, −0.61 to 0.07 points); P=0.117). At 14 days, 24% of the participants receiving HCQ had ongoing symptoms compared with 30% receiving placebo (P=0.21). Medication adverse effects occurred in 43% of HCQ group compared to 22% in the placebo group (P < 0.001).

Abbreviations: HCQ, hydroxychloroquine; CQ, chloroquine; OD, one a day; BD, twice a day; TD, thrice a day; CI, confidence interval; EC50, Half maximal effective concentration; CC50, 50% cytotoxic concentration. SI, selectivity index.

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