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. 2021 Mar 26;39(2):159–170. doi: 10.1016/j.ijmmb.2021.03.002

Table 1.

Details and characteristics of studies.

STUDY TYPE OF STUDY NUMBER OF PARTICIPANTS (TEST VS CONTROL) INTERVENTION PRIMERY OUTCOME OUTCOME MEASURES CONCLUSION
(A)
Wei tang et al.
BMJ, May 2020		 Multi-center open-label Randomized controlled trail 150 (75 vs 75) HCQ loading dose of 1200 mg daily for three days f/b maintenance dose 800 mg daily (total treatment duration: two or three weeks for patients with mild tomoderate or severe disease, respectively) Negative conversion by 28 days with median time for conversion Negative conversion by 28 days, median time to negative conversion
Adverse events w HCQ recipients than non-recipients		 HCQ did not resultin a significantly higher probability of negative conversion than standard of care alone
Adverse events were higher with HCQ
(B)
Joshua Geleris et al.
N Engl J Med. 2020 May		 Observational study 1376 (811 vs 545) HCQ 600 mg twice on day 1, then 400 mg daily for a median of 5 days in Covid-19 patients with moderate-to-severe respiratory illness, Time from study baseline to intubation or death (or time of intubation if patient died after intubation) Time from study baseline to intubation or death (or time of intubation if patient died after intubation) HCQ administration was not associated with either a greatly lowered or an increased risk of the composite end point of intubation ordeath. Randomized, controlled trials of HCQ in patients with Covid-19are needed
(C)
Matthieu Mahévas et al.
BMJ2020 May		 Comparative observational study 181 (84 vs 89) HCQ 600 mg/day within48 h of admission to hospital Survival without ICU transferat day 21 Survival without ICU transferat day 21, overall survival, survival without acute respiratory distress syndrome, weaning from oxygen, and discharge from hospital to home or rehabilitation (all at day 21) No effect of HCQ in reducing ICU admissions or deaths at day 21 in patients with covid-19 pneumoniarequiring oxygen. Results do not support the use of HCQ in these patients
(D)
Philippe Gautret et al.
Travel Med Infect Dis. Mar–Apr 2020		 Uncontrolled, non-comparative observational study 80 HCQ 200 mg orally three times a day for ten days with AZI (500 mg on D1 f/b 250 mg a day for the next four day
  • 1)

    Aggressive clinical course requiring oxygen or ICU transfer after at least three days of treatment

  • 2)

    Contagiousness as assessed by PCR and culture

  • 3)

    Length of stay
  • 1)

    Aggressive clinical course requiring oxygen or ICU transfer after at least three days of treatment

  • 2)

    Contagiousness as assessed by PCR and culture

  • 3)

    Length of stay

 Evidence of beneficial effect of co-administration of HCQ with AZI in COVID-19 treatment and its potential effectiveness in the early reduction of contagiousness.
(E)
Eli S. Rosenberg et al. JAMA. May 2020		 Retrospective multicenter cohort study 1438
735(HCQ ​+ ​AZI) vs 271 (HCQ) vs 211 (AZI)
vs 221(none)		 Retrospective data collection In-hospital mortality In-hospital mortality. cardiac arrest and abnormal ECG findings (arrhythmia or QT prolongation). Treatment with HCQ, AZI, or both, compared with neither treatment, was not significantly associated with differences in in-hospital mortality
(F)
Matthieu Million et al.
Travel Med Infect Dis. May 2020		 Retrospective analysis 1061 HCQ (200 ​mg three times daily for ten days) ​+ ​AZI (500 ​mg on day 1 followed by 250 ​mg daily for the next four days). 1.Aggressive clinical course requiring oxygen, ICU transferor death after at least three days of treatment, prolongedhospitalization (≥10 days) ii) Contagiousness
as assessed by PCR and culture.
.
  • 1

    Aggressive clinical course requiring oxygen, ICU transfer or death after at least three days of treatment, prolonged hospitalization (≥10 days)

  • 2)

    Contagiousness as assessed by PCR and culture

 HCQ ​+ ​AZ combination before COVID-19complications occur is safe and associated with a very low fatality rate.
(G)
PhilippeGautret et al.
Int J Antimicrob Agents. Mar2020		 Openlabel non-randomized clinical trial 36 (26 vs 10) Oral HCQ sulfate 200 mg, three times per day during ten days Virological clearance at day-6 post-inclusion Virological clearance at day-6 post-inclusion, clearance overtime during the study period, clinical follow-up (body temperature, respiratory rate, length of hospital stay, mortality), occurrence of side effects. Recommend that COVID-19 patients be treated with HCQ and AZI to cure their infection and to limit the transmission of the virus to other people in order to curb the spread of COVID-19 in the world
(H)
Yu, B et al.
Sci China Life Sci, May 2020		 Retrospective study 550 critically ill COVID-19 patients who need mechanical ventilation (48 vs 502) oral HCQ (200 mg twice a
day for 7–10 days)		 Fatality of patients and inflammatory cytokine levels – HCQ on top of the basic treatments is highly effective in reducing the fatality of critically ill patients of COVID-19 through attenuation of inflammatory cytokine storm. Therefore, HCQ should be prescribed as a part of treatment
for critically ill COVID-19 patients, with possible outcome of saving lives
(I)
Joshua Barbosa et al. N Engl J Med. 2020 April		 Prospective randomized controlled trail 63 (33 vs 30) HCQ loading dose 400 mg BD per oral for one to two days and followed by 200 mg–400 mg once
daily dose for subsequent three to four		 Effect of hydroxychloroquine usage on the need to escalate respiratory support, change in lymphocyte count, and change in neutrophil-to-lymphocyte ratio. Hydroxychloroquine administration was associated with an increased need for escalation of respiratory support. There were no benefits of hydroxychloroquine on mortality, lymphopenia, or neutrophil-to-lymphocyte ratio improvement, recommend more judicious prescription of hydroxychloroquine for SARS-CoV-2
(J)
Caleb P. Skipper et al.
Ann Intern Med. 2020		 Randomized, double-blind, placebo-controlled trial 491 (244 vs 247) Oral hydroxychloroquine (800 mg once, followed by 600 mg in 6–8 h, then 600 mg daily for 4 more days) or masked placebo. Ordinal outcome by day 14 of not hospitalized, hospitalized, or intensive care unit stay or death Symptom severity at day 5 and day 14 by 10-point visual analogue scale, nominal incidence of all hospitalizations
and deaths, and incidence of study medicine
withdrawal.		 Hydroxychloroquine did not substantially reduce symptom severity in outpatients with early, mild COVID-19.
(K)
Cavalcanti A.B. et al.
N Engl J Med. 2020 Sept		 multicenter, randomized, open-label, three-group, controlled trial 667 suspected or confirmed Covid-19 (229: 221: 217) 1:1:1 standard care: standard care plus hydroxychloroquine 400 mg twice
daily:
standard care plus hydroxychloroquine 400 mg twice daily
plus azithromycin 500 mg once daily for 7 days		 clinical status at 15 days as assessed with the use of a seven-level ordinal scale
  • •

    Clinical status

  • •

    at 7 days

  • •

    Indication for intubation within

  • •

    15 days;

  • •

    the receipt of supplemental oxygen

  • •

    by a high-flow nasal cannula or

  • •

    noninvasive ventilation between randomization

  • •

    and 15 days;

  • •

    Duration of hospital stay

  • •

    In-hospital

  • •

    Death

  • •

    Thromboembolic complications

  • •

    Acute

  • •

    kidney injury

  • •

    Number of days alive and

  • •

    free from respiratory support up to 15 days.

 In hospitalizes patients with mild-to-moderate Covid-19, hydroxychloroquine, alone or with azithromycin, did not improve clinical status at 15 days
as compared with standard care.
(L)
Olivier Paccoud et al.		 Observational retrospective cohort study 84 (38 vs 46)
Hospitalized mild to severe Covid-19		 HCQ (200 mg tid for 10 days) Time to unfavorable outcome, defined as: death, admission to an intensive care unit, or decision to withdraw or withhold life-sustaining treatments, whichever came first.
  • •

    Time to death

  • •

    Time to hospital discharge for a return home or in an aftercare and rehabilitation unit,

  • •

    Fever and cough at day 5

  • •

    Adverse events

 no significant reduction of the risk of unfavorable outcomes was observed with hydroxychloroquine in comparison to standard of care
(M)
Samia Arshad et al.		 Multi-center retrospective observational study 2541 (None: HCQ: AZI: HCQ ​+ ​AZI)
(409: 1202: 147: 783)		 HCQ: 400 mg twice daily for 2 doses on day 1, followed by 200 mg twice daily on days 2–5. AZI: 500 mg once daily on day 1 followed by 250 mg once daily for the next 4 days. Combination severe COVID-19 patients In-hospital mortality, assess treatment experience with HCQ vs HCQ ​+ ​AZI, AZI alone, and other treatments for COVID-19. Hydroxychloroquine alone and in combination with azithromycin was associated with reduction in COVID-19 associated mortality
(N)
Jean-Christophe Lagier et al.
Travel Medicine and Infectious Disease, 2020 June		 Retrospective comparative study HCQ ​+ ​AZI >3days vs other Rx
3737 (3119 vs 618)		 HCQ (200 mg per oral three times daily for ten days) and AZI (500 mg on day 1 followed by 250 mg daily for the next four days) > 3 days Poor clinical outcome:
Death, transfer to the intensive care unit (ICU), ≥10 days of hospitalization and viral shedding.		 Early diagnosis, early isolation and early treatment of COVID-19 patients, with at least 3 days of HCQ-AZ lead to a significantly better clinical outcome
and a faster viral load reduction than other treatments