Copyright ©The Author(s) 2022.
World J Exp Med. May 20, 2022; 12(3): 44-52
Published online May 20, 2022. doi: 10.5493/wjem.v12.i3.44
Table 1 Different studies on the use of the hydroxychloroquine and azithromycin combination to treat coronavirus disease 2019 infection
Study type
Primary endpoint
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-inclusionVirological 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 timeNot 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 daysChanges in the TTCR of the patients (fever and cough). The appearance of severe adverse reactions was the observation endpointA significant response in temperature, cough, and pneumonia was observed in the HCQS groupA 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 aloneNegative conversion rate of COVID-19 nucleic acid in respiratory-pharyngeal swab on days 7 after randomizationOn 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 groupA 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 series323, 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 definedDeath, discharge, and ventilation rateRates 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 patientsThe 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+AZ11% 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, hypoglycemiaCombination therapy had greater potential for QT prolongation and arrhythmia
Chorin at al[24]Retrospective COVID -19 patients (n = 84) The patients were on HCQS+AZEffect of HCQS/AZ on QTc interval and risk for malignant arrhythmiaDevelopment of ARF was a strong predictor of extreme QTc prolongationTorsade’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 = 1061HCQS+AZ for 3 dAssess worsening and viral shedding persistence and deathGood 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)
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
Age ≥ 68 yrs1
Female sex1
Loop diuretic1
Serum potassium (K+) ≤ 3.5 MEq/L2
Admission QTc ≥ 450 ms2
Acute MI (myocardial infarction)2
≥ 2 QTc prolonging drugs3