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Chloroquine and Hydroxychloroquine With or Without Azithromycin: Selected Clinical Data

Last Updated: August 27, 2020

Chloroquine is approved by the Food and Drug Administration (FDA) for the treatment and prevention of malaria and for the treatment of extraintestinal amebiasis. Hydroxychloroquine is approved by the FDA for the treatment of lupus erythematosus, malaria, and rheumatoid arthritis. Azithromycin is commonly used for the treatment and/or prevention of mycobacterial (nontuberculous) infection, sexually transmitted infections, and various bacterial infections. Azithromycin has primarily been studied for the treatment of COVID-19 when it is used in combination with hydroxychloroquine. The Randomised Evaluation of COVID-19 Therapy (RECOVERY) trial includes an azithromycin monotherapy arm, which is currently enrolling.

The information presented in this section may include data from preprints or articles that have not been peer reviewed. This section will be updated as new information becomes available. Please see ClinicalTrials.gov for more information on clinical trials that are evaluating chloroquine, hydroxychloroquine, and azithromycin.

Randomized Controlled Trials

The Effect of Hydroxychloroquine in Hospitalized Patients with COVID-19: Preliminary Results from a Multicenter, Randomized Controlled Trial

This study has not been peer reviewed.

RECOVERY is an ongoing, open-label, randomized controlled trial with multiple arms, including a control arm; in one arm, participants received hydroxychloroquine. The trial was conducted across 176 hospitals in the United Kingdom and enrolled hospitalized patients with clinically suspected or laboratory-confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Patients with prolonged QTc intervals were excluded from the hydroxychloroquine arm.

Patients were randomized in a 2:1 ratio to receive either the usual standard of care only or the usual standard of care plus hydroxychloroquine or one of the other treatments in the platform trial. Patients in the hydroxychloroquine arm received a loading dose of hydroxychloroquine 800 mg at entry and at 6 hours, followed by hydroxychloroquine 400 mg every 12 hours for the next 9 days or until discharge. The primary outcome was all-cause mortality at Day 28 after randomization.

The trial enrollment ended early on June 5, 2020, after an independent data-monitoring committee recommended reviewing the unblinded data, and the investigators and trial-steering committee concluded that the data showed no beneficial effect of hydroxychloroquine.1

Patient Characteristics

  • Of the 7,513 participants who were eligible for hydroxychloroquine, 1,561 were randomized to receive hydroxychloroquine and 3,155 were randomized to receive standard of care. The remaining participants were randomized to other treatment arms in the study.
  • The mean ages of the hydroxychloroquine arm and the standard of care arm were both 65 years; 41% of the participants were aged ≥70 years.
  • Ninety percent of patients had laboratory-confirmed SARS-CoV-2 infection.
  • Comorbidities were common; 57% of patients had at least one major comorbidity. Diabetes mellitus was present in 27% of patients, heart disease in 26%, and chronic lung disease in 22%.
  • At randomization, 17% of patients were receiving invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO), 60% were receiving oxygen only (with or without noninvasive ventilation), and 24% were receiving neither.
  • The use of azithromycin or another macrolide during the follow-up period was similar in both arms (17% vs. 19%), as was the use of dexamethasone (8% vs. 9%).

Results

  • There was no significant difference in the primary outcome of 28-day mortality between the two arms; 418 patients (26.8%) in the hydroxychloroquine arm and 788 patients (25.0%) in the standard of care arm had died by Day 28 (rate ratio 1.09; 95% CI, 0.96–1.23; P = 0.18).
  • A similar 28-day mortality for hydroxychloroquine patients was reported during the post-hoc exploratory analysis that was restricted to the 4,234 participants (90%) who had a positive SARS-CoV-2 test result.
  • Participants in the hydroxychloroquine arm were less likely to survive hospitalization and had a longer median time to discharge than patients in the standard of care arm. In addition, participants who were randomized to receive hydroxychloroquine and who were not on invasive mechanical ventilation at baseline had an increased risk of requiring intubation and an increased risk of death.
  • At the beginning of the study, the researchers did not record whether a patient developed a major cardiac arrhythmia after study enrollment; however, these data were later collected for 698 patients (44.7%) in the hydroxychloroquine arm and 1,357 patients (43.0%) in the standard of care arm. There were no differences between the arms in the frequency of supraventricular tachycardia, ventricular tachycardia or fibrillation, or instances of atrioventricular block that required intervention.

Limitations

  • The study was not blinded.
  • Information on the occurrence of new major cardiac arrythmia was not collected throughout the entire trial period.

Interpretation

Hydroxychloroquine does not decrease 28-day all-cause mortality when compared to the usual standard of care in hospitalized persons with clinically suspected or laboratory-confirmed SARS-CoV-2 infection. Participants who were randomized to receive hydroxychloroquine had a longer median length of hospital stay, and those who were not on invasive mechanical ventilation at the time of randomization were more likely to require intubation or die during hospitalization if they received hydroxychloroquine.

Randomized Controlled Trial of Hydroxychloroquine and Hydroxychloroquine Plus Azithromycin Among Hospitalized Patients with Mild to Moderate COVID-19 in Brazil

This study was an open-label, three-arm, randomized controlled trial that was conducted in Brazil. The study enrolled hospitalized patients aged ≥18 years with suspected or confirmed cases of mild to moderate COVID-19 and duration of symptoms ≤14 days.

Patients received either standard of care alone, hydroxychloroquine 400 mg twice daily for 7 days (plus standard of care), or hydroxychloroquine 400 mg twice daily plus azithromycin 500 mg daily for 7 days (plus standard of care). The primary outcome was clinical status at Day 15, as assessed by a seven-point ordinal scale among the patients with confirmed COVID-19 (modified intention to treat analysis). Exclusion criteria included the need for >4 L of supplemental oxygen or ≥40% FiO2 by face mask, a history of ventricular tachycardia, or a QT interval ≥480 ms. Steroids, other immunomodulators, and antiviral agents were allowed; 23.3% to 23.9% of patients received oseltamivir.2

Patient Characteristics

  • The analysis included 504 patients with confirmed COVID-19.
  • The mean patient age was 50 years, and 58% of patients were men.
  • At baseline, 58.2% of patients were ordinal level 3 (hospitalized without oxygen), and 41.8% were ordinal level 4 (hospitalized with oxygen).
  • The median time from symptom onset to randomization was 7 days.

Results

  • There was no significant difference between the odds of worse clinical status at Day 15 for patients in the hydroxychloroquine group (OR 1.21; 95% CI, 0.69–2.11; P = 1.00) and patients in the hydroxychloroquine plus azithromycin group (OR 0.99; 95% CI, 0.57–1.73; P = 1.00).
  • There were no significant differences in the secondary outcomes of the three arms, including progression to mechanical ventilation during the first 15 days and mean number of days “alive and free of respiratory support.”
  • A greater proportion of patients who received hydroxychloroquine plus azithromycin (39.3%) or hydroxychloroquine alone (33.7%) experienced adverse events (AEs) than those who received standard of care (22.6%).
  • QT prolongation was more common in patients who received hydroxychloroquine plus azithromycin or hydroxychloroquine alone than in patients in the standard of care alone group, but fewer patients in the standard of care alone group had serial electrocardiographic studies performed during the follow-up period.

Limitations

  • The study was not blinded.
  • The follow-up period was restricted to 15 days.

Interpretation

Neither hydroxychloroquine alone nor hydroxychloroquine plus azithromycin improved clinical outcomes at Day 15 after randomization among hospitalized patients with mild to moderate COVID-19.

Randomized Controlled Trial of Hydroxychloroquine Versus Standard of Care for Mild or Moderate COVID-19

This multicenter, randomized, open-label trial compared hydroxychloroquine 1,200 mg once daily for 3 days followed by hydroxychloroquine 800 mg once daily for the rest of the treatment duration (which was 2 weeks for patients with mild or moderate COVID-19 [99% of the patients] and 3 weeks for two patients with severe disease) to standard of care.3

Results

  • Each study arm enrolled 75 patients. Patients were randomized at a mean of 16.6 days after symptom onset.
  • The hydroxychloroquine arm and the standard of care arm had similar negative polymerase chain reaction (PCR) conversion rates within 28 days (85.4% of participants vs. 81.3% of participants) and similar times to negative PCR conversion (median of 8 days vs. 7 days).
  • There was no difference in the probability of symptom alleviation between the groups in the intention-to-treat analysis.

Limitations

  • It is unclear how the overall rate of symptom alleviation was calculated.
  • The study did not reach the target sample size.

Interpretation

This study demonstrated no difference in the rate of viral clearance between hydroxychloroquine and standard of care.

High-Dose Versus Low-Dose Chloroquine

A randomized, double-blind, Phase 2b study compared two different chloroquine regimens, chloroquine 600 mg twice daily for 10 days (high dose) and chloroquine 450 mg twice daily for 1 day followed by 450 mg for 4 days (low dose), in hospitalized adults with suspected cases of severe COVID-19. All patients also received ceftriaxone plus azithromycin; 89.6% of patients received oseltamivir.4

The planned study sample size was 440 participants. The study was stopped by the study’s data safety monitoring board after 81 patients were enrolled.

Results

  • Forty-one and 40 patients were randomized into the high-dose and low-dose chloroquine arms, respectively.
  • The overall fatality rate was 27.2%.
  • Mortality by Day 13 was higher in the high-dose arm than in the low-dose arm (death occurred in 16 of 41 patients [39%] vs. in six of 40 patients [15%]; P = 0.03). This difference was no longer significant after controlling for age (OR 2.8; 95% CI, 0.9–8.5).
  • Overall, QTcF >500 ms occurred more frequently in the high-dose arm (18.9% of patients) than in the low-dose arm (11.1% of patients).
  • Two patients in the high-dose arm experienced ventricular tachycardia before death.

Limitations

More older patients and more patients with a history of heart disease were randomized to the high-dose arm than to the low-dose arm.

Interpretation

Despite the small number of patients enrolled, this study raises concerns about an increased risk of mortality when high-dose chloroquine (600 mg twice daily) is administered in combination with azithromycin and oseltamivir.

Randomized Placebo-Controlled Trial of Hydroxychloroquine in Nonhospitalized Adults with Early COVID-19

This randomized placebo-controlled trial in the United States and Canada enrolled participants with ≤4 days of symptoms that were compatible with COVID-19 and either laboratory-confirmed SARS-CoV-2 infection or high-risk exposure within the previous 14 days. Participants were recruited through internet-based surveys. They were randomized to receive hydroxychloroquine (800 mg once, followed by 600 mg in 6 to 8 hours, and then 600 mg daily for 4 days) or placebo (with the same dosing frequency).

The planned primary endpoint was ordinal outcome by Day 14 in four categories: not hospitalized, hospitalized, intensive care unit (ICU) stay, or death. Due to lower than expected event rates, a new primary endpoint was defined: change in overall symptom severity over 14 days (assessed on a 10-point, self-reported, visual analog scale). A longitudinal mixed model that was adjusted for baseline severity score was used for the anaylsis.5

Patient Characteristics

  • Data were collected from 423 participants (212 in the hydroxychloroquine arm and 211 in the placebo arm) for the primary end point.
  • Of the 423 participants, 241 were exposed to people with COVID-19 through their position as health care workers (57%), 106 were exposed through household contacts (25%), and 76 had other types of exposure (18%).
  • The median age was 40 years, and 56% of patients were women. Only 3% of patients were Black. Very few patients had comorbidities: 11% had hypertension, 4% had diabetes, and 68% had no chronic medical conditions.
  • Fifty-six percent of patients were enrolled on Day 1 of symptom onset.
  • In this study, 341 participants (81%) had either a positive PCR result or a high-risk exposure to a PCR-positive contact.

Results

  • Compared to the placebo recipients, hydroxychloroquine recipients had a nonsignificant 12% difference in improvement in symptoms between baseline and Day 14 (-2.60 vs. -2.33 points; P = 0.117).
  • Ongoing symptoms were reported by 24% of those on hydroxychloroquine and 30% of those in the placebo group at Day 14 (P = 0.21).
  • There was no difference in the incidence of hospitalization (four patients in the hydroxychloroquine group vs. 10 patients in the placebo group). Two of the 10 placebo participants were hospitalized for reasons that were unrelated to COVID-19.
  • A higher percentage of patients who received hydroxychloroquine experienced AEs (mostly gastrointestinal) than patients who received placebo (43% vs. 22%; P < 0.001).

Limitations

  • This study enrolled a highly heterogenous participant population. Only 227 of the 423 participants (53.7%) were confirmed PCR-positive for SARS-CoV-2.
  • Changing the primary endpoint during the study without a new power calculation makes it difficult to assess whether the study is powered to detect differences in outcomes between the study arms.
  • This study used surveys for screening, symptom assessment, and adherence reporting.
  • The visual analog scale has not been commonly used, and its ability to assess acute viral respiratory infections in clinical trials has not been validated.

Interpretation

The study has some limitations, and it did not find evidence that early administration of hydroxychloroquine reduced symptom severity in patients with mild COVID-19.

Open-Label Randomized Controlled Trial of Hydroxychloroquine in Nonhospitalized Adults with Mild COVID-19

This open-label randomized controlled trial in Spain enrolled nonhospitalized adults with laboratory-confirmed SARS-CoV-2 infection and <5 days of mild COVID-19 symptoms. Participants were mostly health care workers. They were randomized to receive hydroxychloroquine (800 mg on Day 1, followed by 400 mg once daily for 6 days) or no antiviral treatment (control group). The primary endpoint was reduction in SARS-CoV-2 viral load, which was assessed using nasopharyngeal swabs on Days 3 and 7. Secondary endpoints were disease progression up to Day 28 and time to complete resolution of symptoms.6

Patient Characteristics

  • Of 353 participants who were randomized to the hydroxychloroquine group or the control group, 60 were excluded from the intention to treat analysis because of negative baseline reverse transcription-PCR (RT-PCR), missing RT-PCR at all follow-up visits, or consent withdrawal.
  • The intention to treat analysis included 293 patients (157 in the control group and 139 in the hydroxychloroquine group). Mean age was 41.6 years, and 67% of patients were female.
  • The majority of patients were healthcare workers (87%), and 53% reported chronic health conditions.
  • The median time from symptom onset to enrollment was 3 days (IQR 2–4 days). The most commonly reported COVID-19 symptoms were fever, cough, and sudden olfactory loss.

Results

  • There was no significant difference in viral load reduction between the control group and hydroxychloroquine group at Day 3 (-1.41 vs. -1.41 log10 copies/mL; difference of 0.01; 95% CI, -0.28 to 0.29), or at Day 7 (-3.37 vs. -3.44 log10 copies/mL; difference of -0.07; 95% CI, -0.44 to 0.29).
  • There was no difference in the risk of hospitalization between the two groups: 7.1% vs. 5.9% (risk ratio 0.75; 95% CI, 0.32–1.77).
  • There was no difference in the median time from randomization to the resolution of COVID-19 symptoms between the two groups (12.0 days in the control arm vs. 10.0 days in the hydroxychloroquine arm; P = 0.38).
  • A higher percentage of participants in the hydroxychloroquine arm than in the control arm experienced AEs during the 28-day follow-up period (72% vs. 9%). The most common AEs were gastrointestinal disorders and “nervous system disorders.”
  • Serious AEs were reported in 12 patients in the control group and in eight patients in the hydroxychloroquine group. The serious AEs that occurred among the hydroxychloroquine patients were not deemed to be related to the drug.

Limitations

  • This was an open-label, non-placebo-controlled trial. The study design allowed for the possibility of drop-outs in the control arm and over-reporting of AEs in the hydroxychloroquine arm.
  • There was a change in the intervention during the study; the authors initially planned to include a combination of hydroxychloroquine and darunavir/cobicistat.
  • The majority of the participants were relatively young health care workers.

Interpretation

Early administration of hydroxychloroquine to patients with mild COVID-19 disease did not result in improvement in virologic clearance, a lower risk of disease progression, or a reduced time to symptom improvement.

Observational Studies

New York Department of Health Study on Hydroxychloroquine With or Without Azithromycin

A retrospective, multicenter, observational study evaluated the use of hydroxychloroquine with and without azithromycin in a random sample of 1,438 inpatients with COVID-19. Patients were categorized into four treatment groups: hydroxychloroquine plus azithromycin, hydroxychloroquine alone, azithromycin alone, or neither drug. The primary outcome measure was in-hospital mortality, and the secondary outcome measure was cardiac arrest and arrhythmia or QT prolongation on an electrocardiogram.7

Results

  • Patients in the three treatment groups had more severe disease at baseline than those who received neither drug.
  • In adjusted analyses, patients who received one of the three treatment regimens did not show a decreased in-hospital mortality rate when compared with those who received neither drug.
  • Patients who received hydroxychloroquine plus azithromycin had a greater risk of cardiac arrest than patients who received neither drug (OR 2.13; 95% CI, 1.12–4.05).

Limitations

Despite the large size of this study, it has the inherent limitations of an observational study. These include residual confounding from confounding variables that were unrecognized and/or unavailable for analysis.

Interpretation

Despite the limitations discussed above, these findings suggest that although hydroxychloroquine and azithromycin are not associated with an increased risk of in-hospital death, the combination of hydroxychloroquine and azithromycin may be associated with an increased risk of cardiac arrest.

Observational Study of Hydroxychloroquine at a Large Medical Center in New York City

This observational study evaluated 1,376 consecutive adults hospitalized with COVID-19. The study assessed the time from study baseline (24 hours after patients arrived at the emergency department) to intubation or death based on whether the patient received hydroxychloroquine at baseline or during follow-up. Patients who received hydroxychloroquine were prescribed a twice-daily dose of hydroxychloroquine 600 mg on the first day followed by 400 mg daily for 4 additional days; this was based on a clinical guidance protocol for the hospital.8

Results

  • In this study, 811 patients (58.9%) received hydroxychloroquine and 565 (41.1%) did not.
  • Hydroxychloroquine recipients were more severely ill at baseline than those who did not receive hydroxychloroquine.
  • Using propensity scores to adjust for major predictors of respiratory failure and inverse probability weighting, the study demonstrated that hydroxychloroquine use was not associated with intubation or death (HR 1.04; 95% CI, 0.82–1.32).
  • There was also no association between concomitant use of azithromycin and the composite endpoint of intubation or death (HR 1.03; 95% CI, 0.81–1.31).

Limitations

Despite the large size of this study, it has the inherent limitations of an observational study. These include residual confounding from confounding variables that were unrecognized and/or unavailable for analysis.

Interpretation

The use of hydroxychloroquine for treatment of COVID-19 was not associated with harm or benefit in a large observational study

Observational Cohort of Hydroxychloroquine Versus No Hydroxychloroquine

This observational, retrospective cohort study analyzed data for adult patients who were hospitalized for severe COVID-19 pneumonia at four French tertiary care centers. The primary outcome was survival without transfer to the ICU at Day 21. An inverse probability of treatment weighting approach was used to “emulate” randomization.9

Results

  • Of the 181 patients who were eligible for the analysis, 84 participants received hydroxychloroquine within 48 hours, eight received hydroxychloroquine beyond 48 hours, and 89 did not receive hydroxychloroquine.
  • In the hydroxychloroquine group, 18% of the patients received concomitant azithromycin.
  • In the inverse probability of treatment weighted analysis, there was no difference in survival rates without ICU transfer at Day 21 between the hydroxychloroquine group (76% of participants) and the non-hydroxychloroquine group (75% of participants). Similarly, there was no difference between the groups in the secondary outcomes of survival rate and survival rate without acute respiratory distress syndrome at Day 21.

Limitations

This was a retrospective, nonrandomized study.

Interpretation

In this retrospective study, there was no difference in the rates of clinically important outcomes between patients who received hydroxychloroquine within 48 hours of hospital admission and those who did not.

Retrospective Cohort Study that Compared Hydroxychloroquine to No Hydroxychloroquine in a Health Care System in Detroit, Michigan

A comparative, retrospective cohort study assessed the outcomes for all consecutive patients who were hospitalized for COVID-19 (which was defined as a positive SARS-CoV-2 PCR from a nasopharyngeal sample) from March 10 to May 2, 2020, in the Henry Ford Health System in Michigan.10

The primary outcome was in-hospital mortality. The study compared outcomes for patients who received hydroxychloroquine alone, hydroxychloroquine plus azithromycin, azithromycin alone, or neither drug.

An interdisciplinary task force of the health system established a COVID-19 treatment protocol that incorporated the use of hydroxychloroquine alone or in combination with azithromycin. The hydroxychloroquine dose was 400 mg twice daily for 1 day, then 200 mg twice daily for 4 days. If azithromycin was used, the dose was azithromycin 500 mg for one day, then 250 mg daily for 4 days. The combination of hydroxychloroquine and azithromycin was reserved for patients with severe COVID-19 and minimal cardiac risks. The clinical treatment protocol allowed for the use of tocilizumab and corticosteroids in some patients; however, the criteria for their use were not specified in the report.

Study Population

  • The analysis included 2,541 consecutive patients.
  • The median patient age was 64 years (IQR 53–76 years); 51% of patients were male, 56% were African American, and 52% had a BMI ≥30.
  • The median time to follow-up was 28.5 days (IQR 3–53 days).
  • The modified sequential organ failure assessment (mSOFA) score was not available for 25% of patients.
  • Corticosteroids were given to 79% of patients in the hydroxychloroquine alone group, 74% of patients in the hydroxychloroquine plus azithromycin group, and 35.7% of those on neither drug.

Mortality

  • Overall, crude mortality was 18.1%. When broken down by the different groups, the mortality was 13.5% in hydroxychloroquine alone group, 20.1% in the hydroxychloroquine plus azithromycin group, 22.4% in the azithromycin alone group, and 26.4% in the group that received neither drug (P < 0.001).
  • Mortality HRs were analyzed using a multivariable Cox regression model; the group that received neither drug was used as the reference. Hydroxychloroquine alone decreased the mortality HR by 66% (P < 0.001). Hydroxychloroquine plus azithromycin decreased the mortality HR by 71% (P < 0.001).
  • Other predictors of mortality were age ≥65 years (HR 2.6; 95% CI, 1.9–3.3); White race (HR 1.7; 95% CI, 1.4–2.1); chronic kidney disease (HR 1.7; 95% CI, 1.4–2.1); reduced O2 saturation level on admission (HR 1.6; 95% CI, 1.1–2.2); and ventilator use at admission (HR 2.2; 95% CI, 1.4–3.0).
  • A propensity-matched Cox regression result suggested a mortality HR of 0.487 for patients who received hydroxychloroquine (95% CI, 0.285–0.832, P = 0.009).

Limitations

  • This retrospective observational study evaluated one health care system with an institutional protocol for hydroxychloroquine and azithromycin use.
  • Because the study was not randomized and not blinded, there is a possibility of residual confounding
  • There was a lower rate of ICU admission among patients who did not receive hydroxychloroquine, which suggests that this group may have received less-aggressive care.
  • A substantially higher percentage of patients in the hydroxychloroquine arms also received corticosteroids compared to the control arm (77.1% vs. 35.7%). Given that the RECOVERY trial showed that dexamethasone use conferred a survival benefit (see Corticosteroids), it is possible that the findings were confounded by this imbalance in corticosteroid use.11

Interpretation

This retrospective, propensity-matched cohort study reported a mortality benefit in hospitalized patients with COVID-19 who received either hydroxychloroquine alone or hydroxychloroquine plus azithromycin compared to receiving neither drug. However, there were substantial imbalances in corticosteroid use between the groups, which may have affected mortality. Moreover, because the study was retrospective and observational, it cannot control for other and unknown confounders.

Other Reviewed Studies

The COVID-19 Treatment Guidelines Panel (the Panel) has reviewed other clinical studies of hydroxychloroquine with or without azithromycin and studies of chloroquine for the treatment of COVID-19.12-17 These studies have limitations (e.g., the potential for residual confounding, small sample sizes, incomplete reporting, a lack of comparison groups) that make them less definitive and informative than large randomized clinical trials. The Panel’s summaries and interpretations of those studies are available in the archived versions of the COVID-19 Treatment Guidelines.

References

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  8. Geleris J, Sun Y, Platt J, et al. Observational study of hydroxychloroquine in hospitalized patients with COVID-19. N Engl J Med. 2020. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32379955.
  9. Mahevas M, Tran VT, Roumier M, 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. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32409486.
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  11. Recovery Collaborative Group, Horby P, Lim WS, et al. Dexamethasone in hospitalized patients with COVID-19—preliminary report. N Engl J Med. 2020. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32678530.
  12. Chorin E, Dai M, Shulman E, et al. The QT interval in patients with COVID-19 treated with hydroxychloroquine and azithromycin. Nature Medicine. 2020. Available at: https://doi.org/10.1038/s41591-020-0888-2.
  13. Gautret P, Lagier JC, Parola P, 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. 2020:101663. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32289548.
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