Hydroxychloroquine (HCQ) sulfate plus Azithromycin |
36 patients |
Patients were grouped into three categories: asymptomatic (16.7 %), upper respiratory tract infection (URTI) when they had rhinitis, pharyngitis or fever (61.1 %) and low-grade myalgia, and lower respiratory tract infection (LRTI) when they had symptoms of pneumonia or bronchitis (22.2 %). |
As determined by RT-PCR on day 6 after inclusion, 70 % of patients treated with HCQ were virologically cured compared to 12.5 % in the control group. |
HCQ or HCQ plus azithromycin were effective for complete eliminating of viral nasopharyngeal load in three to six days. |
France |
a) HCQ: 20 patients received 200 mg of oral HCQ 3 times/ day for 10 days. Among the patients treated with HCQ, six received 500 mg of azithromycin on day 1, followed by 250 mg daily for the next 4 days. |
Gautret et al. (2020aGautret P, Lagier JC, Parola P, Hoang VT, Meddeb L, Mailhe M, et al. Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial. Int J Antimicrob Agents . 2020a;56(1):105949.) |
b) control group: 16 patients who refused the treatment or had an exclusion criteria. |
The primary endpoint was the virologic clearance on day 6 after inclusion. Secondary outcomes were extra time for virologic clearance, clinical follow-up (body temperature, respiratory rate, hospitalization, and mortality) and side effects. |
100 % of patients treated with HCQ plus azithromycin were virologically cured when compared to 57.1 % in patients treated only with HCQ and 12.5 % in the control group. |
Drug’s effect was better in patients with symptoms of URTI and LRTI in comparison with asymptomatic ones. |
Patients with retinopathy, glucose-6-phosphate dehydrogenase (G6PD) deficiency prolongation of QT interval, breastfeeding, and pregnant were excluded. |
COVID-19 patients can receive HCQ plus azithromycin to treat infection and limit virus transmission. |
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HCQ sulfate plus Azithromycin |
600 mg of HCQ daily for 10 days plus 500 mg azithromycin on day 1, followed by 250 mg/ day for the next 4 days. |
At the beginning of treatment, 10 of 11 patients had a fever and received nasal oxygen therapy. |
In 5 days, 1 patient died, two were transferred to the intensive care unit (ICU); HCQ plus azithromycin were discontinued in one after 4 days due to the increasing QT interval from 405 ms to 460 and 470 ms. |
Repeated tests with nasopharyngeal swabs in 10 patients by RT-PCR revealed positivity for SARS-CoV-2 in 8 of them on days 5 or 6 after the start of treatment. Despite in vitro antiviral activity of CQ against COVID-19, no evidence of clinical benefit was found after combination of HCQ and azithromycin. |
France |
7 men and 4 women: 8 with comorbidities (obesity: 2; solid cancer: 3; hematological cancer: 2; HIV infection: 1). |
The mean plasma [HCQ] was 678 ng/mL between days 3 and 7. |
Molina et al. (2020Molina JM, Delaugerre C, Le Goff J, Mela-Lima B, Ponscarme D, Goldwirt L, et al. No evidence of rapid antiviral clearance or clinical benefit with the combination of hydroxychloroquine and azithromycin in patients with severe COVID-19 infection. Méd Mal Infect. 2020;50(4):384.) |
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Chloroquine diphosphate |
81 patients |
Hospitalized patients with respiratory and heart rates > 24 rpm and/or> 125 bpm (without fever) and/or peripheral oxygen saturation < 90 % in room air and/or shock (mean arterial pressure < 65 mmHg, requiring vasopressors or oliguria or low level of consciousness). |
11 patients from the high dose [7 (63.6 %)] and 4 (36.4 %) in the low dose group died. The majority [62 of 81 (76.5 %)] showed COVID-19 confirmed in similar percentages in both groups. Creatine kinase and creatine phosphokinase isoenzyme MB increased by 39.4 % (13 of 33) and 38.4 % (10 of 26 patients), respectively. |
Only 6 patients (22 %) (samples paired in both arms of the study) presented negative respiratory secretion on day 4. |
Ceftriaxone Azithromycin Oseltamivir (standard treatment) |
a) 41 patients: high dose group, CQ (600 mg/4x150 mg, twice a day for 10 days), total of 12 g; |
b) 40 patients: low dose group, CQ (450 mg CQ/3x150 mg + 1 placebo) 2 times daily on day 0, 3x150 mg tablets + 1 placebo followed by 4 placebo tablets from days 1 to 4. Afterwards, 4 placebo tablets 2 times daily from day 5 to day 9, total of 2.7 g. |
The primary outcome (reduction of lethality) assumed a lethality of 20 % in critical patients. Virologic measures included detection of viral RNA by qRT-PCR on days 0 and 4. The final lethality analysis was determined until day 28 and adverse effects and temporary or permanent discontinuation were also observed. |
Increasing of creatine kinase was more frequent in patients under higher of CQ (50 %) than in the low dose group (31.6 %). The mortality rate was 27.2 %. 19 of out 22 dead patients had confirmed antemortem virology. |
The higher dosage of CQ for 10 days was associated with more toxic effects and lethality and cancelled. This dosage is not recommended to treat patients with severe COVID-19, mainly because old aging patients are the most common participants. No benefit with CQ was observed in relation to lethality. |
Brazil |
All patients who met the same study criteria (acute respiratory distress syndrome) received ceftriaxone (1 g 2x for 7 days) + azithromycin (500 mg 1x for 5 days) from day 0. Oseltamivir (75 mg 2x for 5 days) was also prescribed when influenza infection was suspected. |
Borba et al. (2020Borba MGS, Val FFA, Sampaio VS, Alexandre MAA, Melo GC, Brito M, et al. 2020. Effect of high vs low doses of chloroquine diphosphate as adjunctive therapy for patients hospitalized with Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection a randomized clinical trial. JAMA Network Open. 2020;3(4):e208857.) |
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Hydroxychloroquine plus Azithromycin |
1376 patients |
COVID-19 patients with moderate to severe degrees of respiratory disease, defined as an oxygen saturation at rest < 94 % while breathing ambient air. Patients were included in the study if admitted to the emergency sector up to 48 h before. |
Among the 1376 patients, respiratory failure appeared in 346 individuals (25.1 %); a total of 180 patients were intubated and 166 died without intubation. As of April 25th, 232 patients had died (66 after intubation), 1025 had survived (hospital discharge), and 119 were hospitalized yet. |
The risk of intubation or death was not significantly higher or lower among patients who received HCQ or azithromycin when compared to the those who did not. Therefore, the clinical guide of the hospital was updated and the indication HCQ was removed. |
Remdesivir Sarilumab (other concomitant studies/treatments) |
a) 811 received HCQ 600 mg 2x on day 1, followed by 400 mg daily for 4 days. Azithromycin 500 mg on day 1 and then 250 mg/day for additional 4 days in combination with HCQ was an additional suggestion therapeutic option. |
b) 565 patients: control group |
Regression studies showed no association between HCQ and lower risk of intubation or death. |
The results do not indicate the use of HCQ except in randomized clinical trials to test its effectiveness. |
United States |
Multivariate models were used with inverse probability weighting and adjusted for confounding factors using propensity score. |
Geleris et al. (2020Geleris J, Sun Y, Platt J, Zucker J, Baldwin M, Hripcsak G, et al. Observational study of hydroxychloroquine in hospitalized patients with Covid-19. N Engl J Med . 2020;382(25):2411-18.) |
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Hydroxychloroquine plus Azithromycin |
Oral HCQ: 200-600 mg/day, 1 to 2 times/day; azithromycin: 200-500 mg/day, oral or i.v. 1 to 2 times a day. |
Information was collected about the diagnosis of COVID-19, patient demographic data, pre- existing medical conditions, initial vital signs and results of laboratory tests within 24 h after admission and chest images. |
Patients who received HCQ plus azithromycin (30.7 %; 27.1 %) or HCQ (19.2 %; 18.8 %) presented higher levels of intensive care unit (ICU) admission and necessity for mechanical ventilation than those who received azithromycin alone (10.9 %; 6.2 %) and no medication (12.2 %; 8.1 %), respectively, even after statistical adjustment. Mortality adjusted at 21 days was 22.5 % for HCQ + azithromycin, 18.9 % for hydroxychloroquine, 10.9 % for azithromycin, and 17.8 % without drugs. |
Obese, patients with pulmonary and cardiovascular disease and diabetics were more likely to receive HCQ + azithromycin and HCQ alone. Approximately 95 % of the HCQ + azithromycin group presented 3 imaging findings: lung opacity (63 %), pulmonary infiltrate (23.8 %) and bronchopneumonia/ pneumonia (20.7 %). |
1438 patients |
a) 735: received HCQ and azithromycin; |
Most patients (70 %) received HCQ alone and/or azithromycin. |
United States |
b) 271: HCQ |
Among hospitalized patients, treatment with HCQ, azithromycin, or both, did not reduce mortality. |
c) 211: azithromycin |
The primary outcome was hospital mortality. Additional secondary outcomes included cardiac arrest and abnormal electrocardiographic (ECG) findings (arrhythmia or prolonged fraction of the QT interval). |
Patients who received HCQ + azithromycin suffered from cardiac arrest (15.5 %) and abnormal ECG findings (27.1 %), as well as those in the HCQ group alone (13.7 and 27.3 %) compared to azithromycin alone (6.2 and 16.1 %) or no medication (6.8 and 14 %, respectively). |
Rosenberg et al. (2020Rosenberg ES, Dufort EM, Udo T, Wilberschied LA, Kumar J, Tesoriero J, et al. Association of treatment with hydroxychloroquine or azithromycin with in-hospital mortality in patients with COVID-19 in New York state. JAMA 2020;323(24):2493-502.) |
d) 221: no drug (control) |
Cardiac arrest events were more frequent in patients who received HCQ with azithromycin compared to patients who did not receive any medication, even after statistical adjustment. |
Chloroquine was originally planned for the study, but the first selected 573 records indicated limited use and patients who received CQ were later excluded from the study. |
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Hydroxychloroquine |
HCQ 1200 mg/day for 3 days, followed by a maintenance dose of 800 mg/day. The total duration of treatment was 2 weeks for mild and moderate cases and 3 weeks for severe ones. |
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Antiviral agents |
HCQ dose was adjusted when related-drug adverse events arose. |
Diagnosis of mild disease included patients with slight symptoms, and absence of pneumonia by imaging; moderate ones included fever, cough, sputum and other respiratory problems or nonspecific symptoms and pneumonia confirmed by image; severe cases had severe pneumonia defined as the SaO2/SPO2 < 94 % or PaO2/FIO2 ratio of 300 or less. |
The probability of negative conversion of SARS-CoV-2 among patients with standard treatment plus HCQ was 85.4 % in 28 days and similar to the standard group (81.3 %). The most common adverse event in the HCQ group was diarrhea in 10 % of the patients. |
There were no additional benefits to eliminate SARS-CoV-2 after adding HCQ to standard treatment in patients with mild to moderate forms of COVID-19. Overall, these data do not indicate HCQ to treat COVID-19. |
Arbidol |
Lopinavir-ritonavir Entecavir Virazole Ganciclovir (standard treatment varied for each hospital) |
150 patients |
The primary endpoint was the negative conversion of SARS-CoV-2 and clinical improvement within 28 days. The secondary outcome considered adverse events. |
a) 70 patients: HCQ and standard hospital treatment |
The average time for negative conversion, negative conversion in 21 days, symptom relief in 28 days, and average time for relief of clinical symptoms were similar in both groups. |
China |
b) 80 patients: standard hospital treatment only (control) |
Samples from URT, LRT or both were obtained during screening (day -3 to day 1) and during treatment and posttreatment follow-up by visits on days 4, 7, 10, 14, 21 and 28. |
Tang et al. (2020Tang W, Cao Z, Han M, Wang Z, Chen J, Sun W, et al. Hydroxychloroquine in patients with mainly mild to moderate coronavirus disease 2019: open label, randomised controlled trial. BMJ. 2020;369:m1849.) |
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Hydroxychloroquine plus Azithromycin |
200 mg of oral HCQ 3 times daily for 3 days plus azithromycin 500 mg on day 1 followed by 250 mg per day for 4 days. |
Patients were grouped by clinical presentation (symptoms of URTI or LRTI) and severity considering the national early warning score (NEWS) in 3 categories for clinical deterioration: low (NEWS 0-4), medium (NEWS 5-6) and high (NEWS ≥ 7) score. |
The majority did not report any adverse events that could be attributed to the treatment (97.6 %). No rhythmic cardiac events or sudden deaths were observed. |
Considering serum HCQ > 0.1 μg/mL within the therapeutic range, [HCQ] plasma on day 2 (0.20 μg/mL) was lower in the GO group. |
Ceftriaxone Ertapenem Anticoagulants (standard treatment) |
Early treatment with HCQ plus azithromycin with or without symptoms in hospitalized patients or in infectious disease units (hospitalized patients) when necessary. |
High doses of anticoagulants were administered to critically ill patients. |
The primary outcomes were the necessity for oxygen therapy, transfer to the ICU or death after at least 3 days of treatment and prolonged hospitalization (10 days or more). The transmission capacity was assessed by RT-PCR and culture. |
The mean age (69 years) was higher in patients with PClinO than in the GO group (42 years). |
1048 (98.7 %) patients who received the HCQ plus Azithromycin are cured to date. |
1061 patients, excluding < 14 years old, pregnant women or patients with G6PD deficiency (only based on the patient’s declaration). |
Tomographic scores revealed pneumonia in 35 patients from the PClinO group (90 %). |
France |
Patients initially treated in day-care hospital or discharged from conventional wards before day 10 were followed as ambulatory outpatients. |
A group with a poor clinical outcome (PClinO) was defined by death or transfer to the ICU or hospitalization for 10 days or more and a group with a poor virologic result (PVirO) was defined by viral persistence on the 10th day. The others were assigned to a group with good overcomes (GO). |
When compared to patients with GO, PClinO patients were more likely to have previous hypertension (50 %), diabetes (19.6 %), coronary heart disease (19.6 %), and cancer (15.2 %) and more likely receiving beta-blocking agents and angiotensin II receptor blockers, dihydropyridine, HMG-CoA reductase inhibitors, diuretics, and metformin. |
It suggests generalized use of HCQ even in mild cases. |
Million et al. (2020Million M, Lagier JC, Gautret P, Colson P, Fournier PE, Amrane S, et al. Early treatment of COVID-19 patients with hydroxychloroquine and azithromycin: a retrospective analysis of 1061 cases in Marseille, France. Travel Med Infect Dis . 2020;35:101738.) |
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Hydroxychloroquine sulphate plus Azithromycin |
200 mg of HCQ 3 times daily for 3 days plus azithromycin (500 mg on day 1 followed by 250 mg for 4 days. |
Three risk categories for clinical deterioration were stablished: low (NEWS 0-4), medium (NEWS 5-6) and high (NEWS ≥ 7) score. Radiological images classified as compatible (presence of peripheral multifocal opacities in ground glass, with or without cross-links) or presence of alveolar consolidation or mosaic paving pattern or not compatible with pneumonia. |
Most patients presented low NEWS (92 %) and 53.8 % of them had compatible radiological pneumonia images. |
A total of. 57.5 % of patients had at least one chronic condition (hypertension, diabetes, and chronic respiratory diseases were the most frequent) |
France |
80 patients |
The majority (65/80 = 81.3 %) displayed a favorable result and was discharged with low NEWS (61/65 = 93.8 %, but 15 % needed oxygen therapy. A rapid reduction in nasopharyngeal viral load was described by 83 % on day 7. |
Coadministration of HCQ and azithromycin should be early used to treat and cure patients even before irreversible respiratory complications occur, and to slow or prevent the spread of the disease. |
Gautret et al. (2020bGautret P, Lagier JC, Parola P, Hoang VT, Meddeb L, Sevestre J, et al. Clinical and microbiological effect of a combination of hydroxychloroquine and azithromycin in 80 COVID-19 patients with at least a six-day follow up: a pilot observational study. Travel Med Infect Dis. 2020b;34:101663.) |
Nasopharyngeal swabs were collected daily until discharge. Patients were grouped into 2 categories: (i) URTI with isolated rhinitis and/or pharyngitis and/or fever and myalgia and (ii) LRTI with symptoms of pneumonia or bronchitis. |
The primary outcomes: (i) aggressive clinical course with oxygen therapy or transfer to the ICU after at least 3 days of treatment; (ii) transmission assessed by RT-PCR and culture, and (iii) time of hospitalization. |
The presumable contagious declined to zero on day 12. Of the 65 patients discharged, the median time from onset to discharge was 4.1 days, with an average duration of 4.6 days under care for infectious disease. |
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Hydroxychloroquine, Prednisone and Immunosuppressants (standard treatment) |
Oral HCQ 200 - 400 mg/ day for most patients |
SLE patients had to meet the criteria for SLE ratings from the American College of Rheumatology (1997) or those of the 2019 European League Against Rheumatism/ American College of Rheumatology. |
The main comorbidities were obesity and chronic kidney disease in 10 (59 %) and 8 (47 %) of the patients, respectively. |
The average duration of SLE was 8.2 years and the treatment with HCQ before COVID-19 was 7.5 years. |
France |
17 patients with systemic lupus erythematosus (SLE) under long-term treatment with HCQ and confirmed nasopharyngeal SARS-CoV-2 by RT-PCR. |
Viral pneumonia was diagnosed in 13 (76 %), with complications in 16 patients [respiratory failure in 11 (65 %); ARDS in 5 (29 %)]. |
Mathian et al. (2020Mathian A, Mahevas M, Rohmer J, Roumier M, Cohen-Aubart F, Amador-Borrero B, et al. Clinical course of coronavirus disease 2019 (COVID-19) in a series of 17 patients with systemic lupus erythematosus under long-term treatment with hydroxychloroquine. Ann Rheum Dis. 2020;79(6):837-9.) |
Fourteen (82 %) patients were hospitalized, including 7 (41 %) in ICU. Oxygen therapy was required for 11 of them (65 %, nasal cannula and invasive mechanical ventilation). Five (36 %) patients were discharged, seven (50 %) remained hospitalized and two (14 %) died. |
Most SLE patients received long- term treatment with HCQ, whose blood concentrations were within the therapeutic range, which shows that HCQ does not seem to prevent COVID-19 infection. |
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Hydroxychloroquine |
HCQ 600 mg/day |
The start of follow-up (baseline or time zero) for each patient was the time of admission to hospital. All patients were followed-up from baseline until death, loss or end of follow-up, whichever occurred first. |
At day 21, 17 of 173 (10 %) patients had died (9 from the treatment group and 8 from control group). In the nonweighted analyses (and in the inverse probability of treatment weighting analyses that took imbalance at baseline into account), among the 173 patients, the rate of survival without transfer to intensive care, overall survival rate, rate of survival without ARDS, and the oxygen weaning percentage were 80 and 75 % (76 and 75 %), 89 and 91 % (89 and 91 %), 70 and 74 %, (69 and 74 %), and 79 and 74 % (82 and 76 %) at 21 days, respectively, at day 21 for HCQ and control groups. |
Of the 84 patients who received HCQ, eight (10 %) experienced electrocardiographic modifications. These side effects argue against the widespread use of HCQ in patients with COVID-19 pneumonia. |
Azithromycin Amoxicillin-clavulanate (standard treatment) |
181 patients |
France |
a) 84 patients: HCQ within 48 h after hospitalization |
Results also suggested that patients with fewer symptoms and better prognosis at admission did not respond to HCQ. |
Mahévas et al. (2020Mahévas M, Tran VT, Roumier M, Chabrol A, Paule R, Guillaud C, et al. Clinical efficacy of hydroxychloroquine in patients with covid-19 pneumonia who require oxygen: observational comparative study using routine care data. BMJ. 2020;369:m1844.) |
b) 97 patients: control |
The primary outcome was survival without transfer to the ICU at day 21. Secondary outcomes were overall survival, survival without ARDS, weaning from oxygen, and discharge or rehabilitation at day 21. |
HCQ did not reduce ICU transfer or deaths until the 21th day after admission, or ARDS in hospitalized patients with hypoxemic COVID-19 pneumonia. |
Patients with COVID-19 pneumonia requiring oxygen by a face mask or nasal cannula as established by the WHO (progression score 5) were included in the study. |
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Hydroxychloroquine |
The median daily doses [interquartile range (IQR)) of HCQ were 400 (400-480) mg and 422.2 (400-480) mg in the HCQ and HCQ + AZ groups, respectively. The median (IQR) durations of treatment with HC were 5 (3-5) days and 5 (4-6) days in the HC and HC+AZ groups, respectively. |
The outcomes were hospitalization (discharge or death), need for ventilation, type of ventilation, and the result of hospitalization among patients requiring ventilation. Mechanical ventilation included patients receiving both noninvasive and invasive forms of ventilation. |
Of the 807 patients, 124 (15.4 %) died, 517 (64.1 %) were discharged alive, and 166 (20.6 %) remained hospitalized at the end of the study period. After propensity score adjustment for clinical characteristics, the risk of death from any cause was higher in the HQC group but not in the HCQ + AZ group when compared to the no HCQ group (control). |
After adjusting for several relevant confounders, benefits in HCQ groups (with or without azithromycin) were not observed for survival, need for mechanical ventilation, or length of stay among hospitalized COVID-19 patients. |
Azithromycin Compassive therapy (without details) |
807 patients |
United States |
a) 198 patients: HCQ |
Magagnoli et al. (2020Magagnoli J, Narendran S, Pereira F, Cummings TH, Hardin JW, Sutton SS, et al. Outcomes of hydroxychloroquine usage in United States veterans hospitalized with Covid-19. Med. 2020;1(1):114-127.) |
b) 214 patients: HCQ + azithromycin |
For comorbid conditions, it was utilized ICD-10-CM codes and the Charlson comorbidity index. |
The propensity score-adjusted risk of mechanical ventilation was not different after the treatments. Moreover, the length of hospital stay was similar among groups. |
c) 395 patients: no HCQ |
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Hydroxychloroquine or Chloroquine with or without macrolide (Azithromycin or Clarithromycin) |
Within 48 h after the diagnosis of COVID-19, patients received: |
The primary outcome was the association between use of a treatment regimen when initiated early after COVID-19 diagnosis with the endpoint of in-hospital mortality. The secondary outcome was the association between treatment regimens and the occurrence of ventricular arrhythmias during hospitalization [defined as the first occurrence of a nonsustained (at least 6 s) or sustained ventricular tachycardia or ventricular fibrillation]. They also analyzed rates of progression to mechanical ventilation use and length of stay in ICU. |
Nonsurvivors to the treatments were nearly 2-fold for CQ (2.9 %), CQ + azithromycin (7.8 %), HCQ (5.1 %) and HCQ + macrolides (13.8 %) when compared to the control group (1.8, 3.4, 2.9 and 5.6 %), respectively) |
In comparison with the control group (0.3 %), HCQ (6.1 %), HCQ + macrolide (8.3 %), CQ (4.3 %) and CQ + macrolide (6.5 %) groups were independently associated with increased risk of de novo ventricular arrhythmia during hospitalization. |
a) CQ: 1,868 patients (765 mg/6.6 days) |
Lopinavir/Ritonavir Ribavirin Oseltamivir (standard treatment) |
b) CQ + macrolide: 3,783 patients (790 mg/6.8 days) |
United States |
c) HCQ: 3,016 patients (596 mg/4.2 days) |
De novo ventricular arrhythmia (3.7 %), non-ICU length of stay (9.8 days), length of stay in the ICU (9.4 days), total length of stay (19.4 days), and need for mechanical ventilation (42.4 %) were statistically higher in nonsurvivors than in those who survived (1 %, 9 days, 11.1 days and 5.6 %, respectively). |
No evidence of benefit of HCQ or CQ when used either alone or with a macrolide and these regimens were associated with increased risk of ventricular arrhythmias and death, which suggest these therapies should not be used outside of clinical trials. |
Mehra et al. (2020Mehra MR, Desai SS, Ruschitzka F, Patel AN. Retraction - Hydroxychloroquine or chloroquine with or without a macrolide for treatment of COVID-19: a multinational registry analysis. Lancet. 2020;395(10240):1820.) |
d) HCQ + macrolide: 6,221 (597 mg/4.3 days) |
e) Control: 81,144 (none of drugs above) |
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Hydroxychloroquine sulphate |
800 mg HCQ (4 tablets) at once followed by 600 mg 6 - 8 h later, then 600 mg/ day for 4 additional days |
The primary results were symptoms related to COVID-19 based on national guidelines whose cases had been confirmed by RT-PCR, for probable cases (the presence of cough, shortness of breath, or difficulty breathing, or the presence of two or more symptoms of fever, chills, rigors, myalgia, headache, sore throat, and olfactory and taste disorders), and possible cases (the presence of one or more compatible symptoms, which could include diarrhea). |
A total of 87.6 % of volunteers (719/821) had high-risk exposures without using eye shields and surgical masks or respirators. Among them, 365 received HCQ and 354 received placebo. |
There was no difference of symptoms in the group under preventive HCQ intervention if compared to the placebo. |
United States |
821 patients within 4 days of contact: |
COVID-19 (confirmed by PCR or symptoms) developed in 13 % (107/821) during the 14 days. The incidence of new diseases compatible with COVID-19 did not differ significantly between who received HCQ (49/414 = 11.8 %) and placebo (58/407 = 14.3 %). |
No significant changes regarding hospitalization, deaths or the time for onset of postexposure prophylaxis were detected between HCQ and placebo. |
a) 414 patients: HCQ |
Boulware et al. (2020Boulware DR, Pullen MF, Bangdiwala AS, Pastick KA, Lofgren SM, Okafor EC, et al. A randomized trial of hydroxychloroquine as post exposure prophylaxis for Covid-19. N Engl J Med. 2020;383(6):517-25.) |
b) 407 patients: placebo |
Secondary outcomes included the incidence of hospitalization for COVID-19 or death, the incidence of PCR-confirmed SARS-CoV-2 infection, the incidence of COVID-19 symptoms, the incidence of discontinuation of the trial intervention owing to any cause, and the severity of symptoms (if any) at days 5 and 14 according to a visual analog scale [scores ranged from 0 (no symptoms) to 10 (severe symptoms) ]. |
The most common reason for discontinuation was attributed to side effects, which were more frequent in HCQ-treated group than with placebo, but no serious intervention-related adverse reactions or cardiac arrhythmias were noted. |
High doses of HCQ did not prevent the development of COVID-19 when prophylaxis was started within 4 days after high- or moderate-risk exposure. |
Participants have had household or occupational exposure to someone with confirmed COVID-19 at a distance of less than 6 ft for more than 10 min while wearing neither a face mask nor an eye shield (high- risk exposure) or while wearing a face mask but no eye shield (moderate-risk exposure). |
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Hydroxychloroquine sulphate |
a) 244 patients: HCQ 800 mg/day (4 tablets) once; 600 mg/day 6 to 8 h later, and 600 mg (3 tablets) once daily for 4 additional days. |
Nonhospitalized adults who required to have 4 or fewer days of symptoms and either PCR-confirmed SARS-CoV-2 infection or compatible symptoms after a high-risk exposure (immediate household contact or a close occupational COVID-19 exposure) to a person with confirmed PCR within the past 14 days. |
Of 341 persons, 145 were PCR-positive for SARS- CoV-2 and 280 had known high-risk exposure to a PCR-positive contact; 84 had both. The remaining 82 participants (19 %) were enrolled with suspected COVID-19: They had COVID-19-compatible symptoms and reported high-risk exposure. |
Additional post hoc analyses showed that self-reported use of zinc or vitamin C in addition to HCQ did not improve symptoms over use of HCQ alone. |
United States and Canada |
b) 247 patients: placebo (folic acid, 400 ug). |
HCQ failed to decrease prevalence or severity of symptoms over the 14- day study period. |
Skipper et al. (2020Skipper CP, Pastick KA, Engen NW, Bangdiwala AS, Abassi M, Lofgren SM, et al. Hydroxychloroquine in nonhospitalized adults with early COVID-19: A randomized trial. Ann Intern Med. 2020;173(8):623-31.) |
Persons with either laboratory- confirmed COVID-19 or compatible symptoms and contact with laboratory- confirmed COVID-19 person. Follow-up surveys were performed for 14 days to assess study medication adherence, adverse effects, presence and severity of COVID-19 symptoms (0-10 analogic scale), virologic results, and hospitalization. |
The initial primary outcome was an ordinal outcome by day 14 of nonhospitalized, hospitalized, or ICU stay or death. Secondary end points were symptom severity on day 5 and 14 by 10-point visual scale, hospitalizations and deaths, and incidence of study medicine withdrawal. If hospitalized within 14 days, the follow-up continued to assess outcomes. |
On day 5 and 14, 54 and 56 % and 24 and 30 % of participants receiving HCQ and placebo reported symptoms, respectively. |
The incidence of hospitalization or death did not differ between treated and placebo groups. |
HCQ (2.60 points) and placebo (2.33 points) groups had a similar and not significant mean reduction of points from baseline on the 10-point visual analog scale for symptom severity. |
Adverse effects were more common in HCQ than placebo through the 5-day regimen (43 % vs. 22 %, p < 0.001). |
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Hydroxychloroquine Azithromycin |
HCQ 400 mg 2x on day 1, followed by 200 mg twice daily on days 2-5. Azithromycin 500 mg on day 1 followed by 250 mg once daily for additional 4 days. Their combination was reserved for selected patients with severe COVID-19 and with minimal cardiac risk factors. |
Admission with a positive SARS-CoV-2 test and data collected from electronic medical records, including demographic and clinical characteristics. |
Multivariable Cox regression analysis showed HCQ alone decreased the mortality hazard ratio by 66 % and HCQ + azithromycin decreased the mortality hazard ratio by 71 %. |
HCQ may have role to play in reducing COVID-19 mortality but such protocol should not be applied to patients outside of hospital settings. |
Corticosteroids and Tocilizumab (standard treatment) |
2541 patients divided into: |
The maximal modified Sequential Organ Failure Assessment (mSOFA) scores on admission were collected. |
Predictors of mortality were age ≥ 65 years, white race, kidney diseases, reduced O2 saturation level on admission, and mechanical ventilation use during admission. |
United States |
a) No drugs: 409 patients |
Arshad et al. (2020Arshad S, Kilgore P, Chaudhry ZS, Jacobsen G, Wang DD, Huitsing K, et al. Treatment with hydroxychloroquine, azithromycin, and combination in patients hospitalized with COVID-19. Int J Infec Dis. 2020;97:396-403.) |
b) HCQ: 1202 |
The primary endpoint was inpatient hospital mortality in each treatment group. |
Kaplan-Meier survival curves within the propensity matched setting displayed better survival in the HCQ treated group, and enhanced survival for 28 days from admission. |
c) Azithromycin: 187 |
d) HCQ + azithromycin: 783 |
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Hydroxychloroquine sulphate |
HCQ 800 mg on day 1, followed by 400 mg once daily for six days |
Participants were assessed on day 1 (baseline, HCQ was started), 3, 7, 14, and 28 for collection of epidemiological and monitoring of disease progression, safety, and self-reported treatment compliance. |
No differences between the control and HCQ groups at day 3 or 7 were observed in relation to the viral load from nasopharyngeal swabs. |
Any meaningful virologic or clinical benefit of HCQ in outpatients with mild COVID-19 was found if HCQ is given within five days from symptom onset. Moreover, this treatment regimen neither reduced the risk of hospitalization nor decreased the time to complete resolution of symptoms. |
293 patients |
The risk of hospitalization was similar in the control (11/157 = 7.1 %) and intervention arm (8/136 = 5.9 %). |
a) Control arm: 157 |
The primary outcome was the reduction of viral load in nasopharyngeal swabs at days 3 and 7. The secondary outcomes were clinical progression measured by a simplified version of the WHO progression scale and resolution time of symptoms within the 28-days follow-up period. Adverse events were assessed up to 28 days. |
Median time for resolution of COVID-19 symptoms was not significantly different between the groups (12 days vs. 10 days.). Twenty serious adverse events were reported (12 vs. 8 in the control and intervention arms, respectively). |
Spain |
b) Intervention arm: 136 patients received HCQ 800 mg on day 1 and 400 mg once daily for 6 days. |
Mitjá et al. (2020Mitjà O, Corbacho-Monné M, Ubals M, Tebe C, Peñafiel J, Tobias A, et al. Hydroxychloroquine for early treatment of adults with mild Covid-19: A randomized-controlled trial. Clin Infect Dis . 2020;ciaa1009.) |
Patients aged 18 years or more with mild symptoms of COVID-19 (i.e., fever, acute cough, shortness of breath, sudden olfactory or gustatory loss, or influenza-like-illness) for less than 5 days before enrollment, nonhospitalized, and positive for SARS-CoV-2. |
The most frequent treatment- related adverse events among participants given HCQ were gastrointestinal. |
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Hydroxychloroquine plus Azithromycin |
665 patients |
The primary outcome was the clinical status at 15 days evaluated by a seven-level severity scale (from 1 to 7) taking into consideration the severity of symptoms, necessity for hospitalization, noninvasive and invasive mechanical ventilation, and death. |
There were no differences among the groups in the proportional odds of having a higher (worse) score on the seven-point ordinal scale at 15 days and need for mechanical ventilation requirements (HCQ + azithromycin: 11 %; HCQ: 7.5 %; control: 6.9 %). |
Thromboembolic or acute kidney injury events, days alive and free from respiratory support were similar among groups within 15 days. |
Glucocorticoids, immunomodulators, antibiotic, and antiviral (standard treatment) |
a) Control: 227 patients (standard treatment) |
b) HCQ 400 mg twice daily for 7 days: 221 patients |
Brazil |
c) HCQ 400 mg 2x daily plus azithromycin at a dose of 500 mg once a day for 7 days: 217 patients |
Secondary outcomes included clinical status at 7 days evaluated by a six-level ordinal scale, and indication for intubation and supplemental oxygen, duration of hospital stays, in-hospital death, thromboembolic complications, acute kidney injury, and number of days alive and free from respiratory support up to 15 days. |
Adverse events were more common in patients who received HCQ + azithromycin (39.3 %) or HCQ alone (33.7 %), as well as prolongation of the QTc interval in HCQ with or without azithromycin. Elevation in liver enzymes was higher in patients receiving HCQ + azithromycin. |
This 7-day course of HCQ either with azithromycin did not result in better clinical outcomes but these regimens were more associated with the occurrence of hepatic damages and more frequent events of QTc interval prolongation. |
Cavalcanti et al. (2020Cavalcanti AB, Zampieri FG, Rosa RG, Azevedo LCP, Veiga VC, Avezum A, et al. Hydroxychloroquine with or without azithromycin in mild-to-moderate Covid-19. N Engl J Med. 2020;383(21):2041-52.) |
It included hospitalized persons with suspected or confirmed COVID-19 with 14 or fewer days of symptom. |