Use of hydroxychloroquine and azithromycin combination to treat the COVID-19 infection

Table 1 Different studies on the use of the hydroxychloroquine and azithromycin combination to treat coronavirus disease 2019 infection

Ref.	Study type	Treatment/duration	Primary endpoint	Outcome	Adverse effects
Gautret et al[16]	Open level non-randomized trial	A total of 36 patients; n = 14 on HCQS 200 mg TDS; n = 6 on HCQS+AZ; n = 16 in the control group	Virological clearance at day 6 post-inclusion	Virological clearance at day 6 post-inclusion in the HCQS group (57%), HCQS+AZ (100%), and in the control group (12%)	Not reported well
Gautret et al[17]	A pilot observational study (n = 80)	Hydroxychloroquine (200 mg every 8 h) for 10 d and azithromycin (500 mg on day 1, 250 mg on days 2-5)	Disease progression: need for oxygen or ICU admission	Viral load decreased over time	Not reported well
Chen et al[18]	Prospective open-label, non-randomized trial (n = 62)	Patients (31) were assigned to receive (400 mg/d) treatment for five days	Changes in the TTCR of the patients (fever and cough). The appearance of severe adverse reactions was the observation endpoint	A significant response in temperature, cough, and pneumonia was observed in the HCQS group	A total of 4 patients out of 62 had severe illness in the control group, and 2 patients had mild illness in the HCQS group
Chen et al[20]	Pilot Study; n = 30 treatment- naive patients with confirmed COVID -19	HCQS group (n = 15); HCQS 400 mg per day for 5 d plus conventional treatments Control (n = 15). Conventional treatment alone	Negative conversion rate of COVID-19 nucleic acid in respiratory-pharyngeal swab on days 7 after randomization	On day 7, COVID-19 nucleic acid of throat swabs was negative in 13 (86.7%) cases in the HCQS group and in 14 (93.3%) cases in the control group	A total of 4 cases (26.7%) from the HCQS group and 3 cases (20%) from the control group had transient diarrhea and abnormal LFT
Lane et al[22]	Cohort and self-control case series	323, 122 hydroxychloroquine plus azithromycin	Severe adverse events, hospital-based events, gastro-intestinal bleeding, acute renal failure, acute pancreatitis, myocardial infarction, stroke, transient ischemic attack, and cardio- vascular events	Azithromycin plus HCQS increased risk of 30-d cardiovascular mortality
Magagnoli et al[29]	Retrospective analysis; (HCQS = 97; HCQS+AZ = 113; Neither = 158)	Dosage and treatment length were not defined	Death, discharge, and ventilation rate	Rates of death in HCQS, HCQS+AZ, and no HCQS groups were 27.8%, 22.1%, and 11.4%, respectively. Rates of ventilation in the HCQS, HCQS+AZ, and no HCQS groups were 13.3%, 6.9%, and 14.1%, respectively
Rosenberg et al[23]	Retrospective multicenter cohort study	1438 hospitalized patients	The primary outcome was in-hospital mortality. Secondary outcomes were cardiac arrest and abnormal electrocardiogram findings (arrhythmia or QTc prolongation)	HCQS+AZ (25.7%), HCQS alone (19.9%), AZ alone (10.0%), and neither drug (12.7%)	A greater proportion of patients receiving HCQS+AZ experienced cardiac arrest (15.5%) and abnormal ECG findings (27.1%), as did those in the HCQS alone group (13.7% and 27.3, respectively), com- pared with azithromycin alone (6.2% and 16.1%, respectively) and neither drug (6.8% and 14.0%, respectively)
Mercuro et al[25]	n = 90; Cohort study	HCQS vs HCQS+AZ	11% had a QTc increase of > 60 ms; 20% had QTc > 500. The median rise in QTc was higher with combination therapy (23 ms vs 5.5 ms). The corresponding rates of QTc > 60 ms were also higher with combination arm (3% vs 13%) as was the rate of QTc > 500 ms (19% vs 21%)	Intractable nausea, premature ventricular complex, right bundle branch block, Torsade’s de pointes, hypoglycemia	Combination therapy had greater potential for QT prolongation and arrhythmia
Chorin at al[24]	Retrospective COVID -19 patients (n = 84)	The patients were on HCQS+AZ	Effect of HCQS/AZ on QTc interval and risk for malignant arrhythmia	Development of ARF was a strong predictor of extreme QTc prolongation	Torsade’s de pointes = 0, QTc increase > 40 ms = 30%; QTc > 500 ms = 11%; Significant QTc prolongation in HCQS = 11%
Million et al[19]	Non-comparative observational study; n = 1061	HCQS+AZ for 3 d	Assess worsening and viral shedding persistence and death	Good clinical outcome and virological cure were obtained in 973 patients within ten days (91.7%)	Poor clinical outcome was observed in 46 patients (4.3%); 8 died (0.75%) (74-95 years old)

HCQS: Hydroxychloroquine; AZ: Azithromycin; COVID-19: Coronavirus disease 2019.

Table 2 Tisdale assessment risk score for drug-associated QTc prolongation. A Tisdale score of < 6 predicts low risk, 7-10 medium risk, and > 11 high risk of drug-associated QT prolongation [Adapted from reference 30]

Risk factors	Points
Age ≥ 68 yrs	1
Female sex	1
Loop diuretic	1
Serum potassium (K+) ≤ 3.5 MEq/L	2
Admission QTc ≥ 450 ms	2
Acute MI (myocardial infarction)	2
≥ 2 QTc prolonging drugs	3