Chloroquine or Hydroxychloroquine
Last Updated: June 16, 2020
- The COVID-19 Treatment Guidelines Panel (the Panel) recommends against the use of chloroquine or hydroxychloroquine for the treatment of COVID-19, except in a clinical trial (AII).
- The Panel recommends against the use of high-dose chloroquine (600 mg twice daily for 10 days) for the treatment of COVID-19 (AI).
The safety and efficacy of chloroquine and hydroxychloroquine have been evaluated in small randomized clinical trials, case series, and observational studies (as described below). Data from large randomized controlled trials are necessary to definitively determine the efficacy of chloroquine and hydroxychloroquine in treating COVID-19.
A large, retrospective, observational study that evaluated the use of hydroxychloroquine has shown no evidence of benefit in patients with COVID-19. Clinical outcomes in that study included death and the need for mechanical ventilation.1 Reports have documented serious dysrhythmias in patients with COVID-19 who were treated with chloroquine or hydroxychloroquine, often in combination with azithromycin and other medicines that prolong the QTc interval. Given the risk of dysrhythmias, the Food and Drug Administration (FDA) cautions against the use of chloroquine or hydroxychloroquine for the treatment of COVID-19 outside of a hospital or clinical trial.2 When chloroquine or hydroxychloroquine is used, clinicians should monitor the patient for adverse effects (AEs), especially prolonged QTc interval (AIII).
High-dose chloroquine (600 mg twice daily for 10 days) has been associated with more severe toxicities than lower-dose chloroquine (450 mg twice daily for 1 day, followed by 450 mg once daily for 4 days). A comparative trial compared high-dose chloroquine and low-dose chloroquine in patients with COVID-19; in addition, all of the participants received azithromycin and 89% of the participants received oseltamivir. The study was discontinued early when preliminary results showed higher rates of mortality and QTc prolongation in the high-dose chloroquine group.3
Chloroquine is an antimalarial drug that was developed in 1934. Hydroxychloroquine, an analogue of chloroquine, was developed in 1946 and is used to treat autoimmune diseases, such as systemic lupus erythematosus (SLE) and rheumatoid arthritis. In general, hydroxychloroquine has fewer and less severe toxicities (including less propensity to prolong the QTc interval) and fewer drug-drug interactions than chloroquine.
Proposed Mechanism of Action and Rationale for Use in Patients with COVID-19
- Both chloroquine and hydroxychloroquine increase the endosomal pH, inhibiting fusion of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the host cell membranes.4
- Chloroquine inhibits glycosylation of the cellular angiotensin-converting enzyme 2 receptor, which may interfere with binding of SARS-CoV to the cell receptor.5
- In vitro, both chloroquine and hydroxychloroquine may block the transport of SARS-CoV-2 from early endosomes to endolysosomes, which may be required for release of the viral genome.6
- Both chloroquine and hydroxychloroquine have immunomodulatory effects.
Clinical Data for COVID-19
The available clinical data on the use of chloroquine and hydroxychloroquine to treat COVID-19 mostly come from use in patients with mild, and in some cases, moderate disease. Clinical data on the use of these drugs in patients with severe and critical COVID-19 are very limited. The clinical data are summarized below.
Please see the Hydroxychloroquine plus Azithromycin section for additional clinical data on hydroxychloroquine.
High-Dose Versus Low-Dose Chloroquine
A randomized, double-blind, Phase 2b study compared two different chloroquine regimens for the treatment of COVID 19: high-dose chloroquine (600 mg twice daily for 10 days) versus low-dose chloroquine (450 mg twice daily for 1 day followed by 450 mg for 4 days). The study participants were hospitalized adults with suspected severe COVID-19 (respiratory rate >24 rpm, heart rate >125 bpm, oxygen saturation <90%, and/or shock).3 All patients received ceftriaxone plus azithromycin; 89.6% of the patients also received oseltamivir. Of note, both azithromycin and oseltamivir can increase the QTc interval.
The primary outcome measure for this analysis was mortality at 13 days after treatment initiation. The planned study sample size was 440 participants, which was enough to show a reduction in mortality by 50% with high-dose chloroquine. The study was stopped by the data safety and monitoring board after 81 patients were enrolled into the study.
- 41 and 40 patients were randomized into the high-dose and low-dose 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 (adds ratio 2.8; 95% confidence interval [CI], 0.9–8.5).
- Overall, QTcF >500 ms occurred more frequently among patients in the high-dose arm (18.9%) than in the low-dose arm (11.1%). Among those with confirmed COVID-19, QTcF >500 ms occurred more frequently in the high-dose arm (24.1%) than in the low-dose arm (3.6%).
- Two patients in the high-dose arm experienced ventricular tachycardia before death.
- 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.
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.
Chloroquine Versus Lopinavir/Ritonavir
In a small randomized, controlled trial in China, 22 hospitalized patients with COVID-19 (none critically ill) were randomized to receive oral chloroquine 500 mg twice daily or lopinavir 400 mg/ritonavir 100 mg twice daily for 10 days.7 Patients with a history of heart disease (chronic disease and a history of arrhythmia), or kidney, liver, or hematologic disease were excluded from participation. The primary study outcome was SARS-CoV-2 polymerase chain reaction (PCR) negativity at Days 10 and 14. Secondary outcomes included improvement of lung computed tomography (CT) scan at Days 10 and 14, discharge at Day 14, and clinical recovery at Day 10, as well as safety (which was determined by evaluating study drug-related AEs).
- 10 patients received chloroquine and 12 patients received lopinavir/ritonavir. At baseline, patients had good peripheral capillary oxygen saturation (SpO2) (97% to 98%).
- Compared to the lopinavir/ritonavir-treated patients, the chloroquine-treated patients had a shorter duration from symptom onset to initiation of treatment (2.5 days vs. 6.5 days, P < 0.001).
- Though not statistically significant, patients in the chloroquine arm were younger (median age 41.5 years vs. 53.0 years, P = 0.09). Few patients had co-morbidities.
- At Day 10, 90% of the chloroquine-treated patients and 75% of the lopinavir/ritonavir-treated patients had a negative SARS-CoV-2 PCR test result. At Day 14, the percentages for the chloroquine-treated patients and the lopinavir/ritonavir-treated patients were 100% and 91.2%, respectively.
- At Day 10, 20% of the chloroquine-treated patients and 8.3% of the lopinavir/ritonavir-treated patients had CT scan improvement. At Day 14, the percentages for the chloroquine-treated patients and the lopinavir/ritonavir-treated patients were 100% and 75%, respectively.
- At Day 14, 100% of the chloroquine-treated patients and 50% of the lopinavir/ritonavir-treated patients were discharged from the hospital.
- The risk ratios of these outcome data cross 1, and the results were not statistically significant.
- Both chloroquine and lopinavir/ritonavir were generally well-tolerated.
- The trial sample size was very small, and the participants were fairly young.
- The chloroquine-treated patients were younger and had fewer symptoms prior to treatment initiation, which are variables that could have affected the study protocol-defined outcomes.
- Patients who had chronic co-morbidities and who were critically ill were excluded from the study.
In this small randomized, controlled trial, chloroquine and lopinavir/ritonavir showed similar efficacy in treating COVID-19.
Observational Study of Hydroxychloroquine at a Large Medical Center in New York City
This observational study evaluated 1,376 consecutive adults with COVID-19 who were admitted to a large New York City hospital (after excluding 70 patients who died or who were transferred within 24 hours after presenting to the emergency department). 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 and 400 mg daily for 4 additional days; this was based on the clinical guidance of the hospital.1
- 811 patients (58.5%) received hydroxychloroquine and 565 (41.1%) did not.
- Patients who received hydroxychloroquine were older and more likely to have hypertension (49.1% vs. 6.7%) and to be on systemic steroids (26.6% vs. 10.1%) compared with those who did not receive hydroxychloroquine.
- Patients who received hydroxychloroquine were more likely to receive concomitant azithromycin (59.9% vs. 22.5%) and/or other antibiotics (74.5% vs. 54.0%) compared with those who did not receive hydroxychloroquine.
- Patients who received hydroxychloroquine had higher levels of inflammatory markers.
- Hydroxychloroquine-treated patients had more severe hypoxia, with a lower PaO2/FiO2 ratio at baseline than patients who did not receive hydroxychloroquine (median of 233 mm Hg vs. 360 mm Hg).
- Most patients (85.9%) received hydroxychloroquine within 48 hours of presentation.
- 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 (hazard ratio [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).
- Despite the large size of this study, it suffers from the inherent limitations of an observational study. These include residual confounding from confounding variables that were unrecognized and/or unavailable for analysis.
The use of hydroxychloroquine for treatment of COVID-19 was not associated with harm or benefit in a large observational study.
Retrospective Observational Cohort from the United States Veterans Health Administration
This study has not been peer reviewed.
An observational, retrospective cohort study analyzed data from patients with confirmed COVID-19 who were hospitalized at the United States Veterans Health Administration medical centers between March 9, 2020, and April 11, 2020.8 Patients were categorized as having received either hydroxychloroquine, hydroxychloroquine plus azithromycin, or no hydroxychloroquine. Doses and duration of hydroxychloroquine or azithromycin use were not specified. All patients also received standard supportive management for COVID-19. The primary endpoints were death and the need for mechanical ventilation. Associations between treatment and outcomes were determined using propensity score adjustment, including demographic, co-morbid, and clinical data (including predictors of COVID-19 disease severity). Patients were included in the analysis if body mass index, vital signs, and discharge disposition were noted in their medical records.
- 368 patients were eligible for analysis. The patients were categorized into three treatment groups: hydroxychloroquine (n = 97; median age of 70 years), hydroxychloroquine plus azithromycin (n = 113; median age of 68 years), or no hydroxychloroquine (n = 158; median age of 69 years). All patients were male.
- 70 patients died; 35 of those who died (50%) were not receiving mechanical ventilation.
- No difference was observed between the groups in the risk of mechanical ventilation.
- Compared to the no hydroxychloroquine group, the risk of death from any cause was higher in the hydroxychloroquine group (adjusted HR 2.61; 95% CI, 1.10–6.17; P = 0.03), but not in the hydroxychloroquine plus azithromycin group (adjusted HR 1.14; 95% CI, 0.56–2.32, P = 0.72).
- There was no between-group difference in the risk of death after ventilation.
- The patient population was entirely male.
- The dose and duration of administration for hydroxychloroquine and azithromycin were not included in the report. Patients were included if they received a single dose of either or both drugs.
- Propensity score adjustment was used to account for differences between the groups, but the possibility of residual confounding cannot be excluded as patients who were more ill may have been more likely to receive hydroxychloroquine.
- No imaging data were presented; severity of chest X-ray findings could predict worse outcomes.
- The use of other antiviral or immunomodulatory agents was not reported.
- The reason for the high mortality rate among patients who did not receive mechanical ventilation is not clear, especially as most of these patients appear to have had mild/moderate disease at admission.
This study showed no beneficial effect of hydroxychloroquine plus azithromycin for the treatment of COVID-19 and a possible association between hydroxychloroquine and increased mortality; however, residual confounding may have affected the study results.
Randomized, Controlled Trial of Hydroxychloroquine Versus Standard of Care for Mild/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 (2 weeks for patients with mild/moderate COVID-19 [99% of the patients] and 3 weeks for two patients with severe disease) versus standard of care (SOC).9
The primary outcome was negative PCR within 28 days. Secondary outcomes were alleviation of symptoms (resolution of fever, SpO2 >94% on room air, resolution of respiratory symptoms), improvement in markers of inflammation (including C-reactive protein),and improvement of lung lesions on a chest X-ray within 28 days.
- 75 patients were enrolled in each study arm. Patients were randomized at a mean of 16.6 days after symptom onset.
- No difference was found between the hydroxychloroquine arm and the SOC arm in negative PCR conversion rate within 28 days (85.4% of participants vs. 81.3% of participants, respectively) or in time to negative PCR conversion (median of 8 days vs. 7 days, respectively).
- There was no difference in the probability of symptom alleviation between the groups in the intention-to-treat analysis.
- AEs occurred in 30% of the participants in the hydroxychloroquine arm (most commonly diarrhea) versus in 9% of the participants in the SOC arm.
- It is unclear how the overall rate of symptom alleviation was calculated.
- The duration of hydroxychloroquine use (2 weeks) was longer than in most other observational cohort studies or clinical trials for the treatment of COVID-19.
- The study did not reach the target sample size.
This study demonstrated no difference in viral clearance between hydroxychloroquine and SOC.
Observational Cohort of Hydroxychloroquine Versus No Hydroxychloroquine
This observational, retrospective cohort study analyzed data for adult patients who were hospitalized for COVID-19 pneumonia at four French tertiary care centers over a 2-week period (March 17–31, 2020). Patients aged 18 to 80 years were eligible if they had PCR-confirmed SARS-CoV-2 infection and required oxygen by mask or nasal cannula. Exclusion criteria included hydroxychloroquine initiation before hospitalization, receipt of another experimental COVID-19 treatment within 48 hours, organ failure that required immediate admission to the intensive care unit (ICU) or continuous care unit, admission with acute respiratory distress syndrome (ARDS) that required noninvasive ventilation with continuous positive airway pressure or mechanical ventilation, discharge from the ICU to standard care, or if a decision was made to limit or stop active treatments that were prescribed at admission. Patients in one treatment arm received a daily dose of hydroxychloroquine 600 mg within 48 hours of admission; patients in the other arm did not receive hydroxychloroquine during the same period. The decision to use hydroxychloroquine to treat a patient was based on local medical consensus and prescriber opinion, and was reportedly independent of patient characteristics. Patients were followed from baseline until death, loss to follow-up, or the end of follow-up on April 24, 2020. 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.10
- 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 participants did not receive hydroxychloroquine.
- Co-morbidities were less common in the hydroxychloroquine group; overall initial COVID-19 severity was well balanced across the treatment arms.
- In the hydroxychloroquine group, 18% of the patients received concomitant azithromycin and 52% of the patients received amoxicillin/clavulanic acid.
- In the inverse probability of treatment weighted analysis, there was no difference in the primary outcome (survival rate 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 and survival without ARDS at Day 21.
- Among the 84 patients who received hydroxychloroquine within 48 hours, eight patients (10%) experienced electrocardiogram (ECG) changes that required treatment discontinuation at a median of 4 days from the start of dosing, including seven patients with a QTc that prolonged >60 ms and one patient with new onset, first-degree atrioventricular block. None of these patients received azithromycin.
- This was a retrospective, nonrandomized study.
In this retrospective study, there was no difference in clinically important outcomes between patients who received hydroxychloroquine within 48 hours of hospital admission and those who did not.
A Case Series of Hydroxychloroquine Versus Control
In a case series from France, 26 hospitalized adults with SARS-CoV-2 infection categorized as asymptomatic or with upper or lower respiratory tract infection who received hydroxychloroquine 200 mg three times daily for 10 days were compared to 16 control individuals (i.e., those who refused treatment, did not meet eligibility criteria, or were from a different clinic).11Results:
- Six patients in the hydroxychloroquine group were excluded from the analysis for the following reasons:
- One patient died.
- Three patients were transferred to the ICU.
- One patient stopped taking the study drug due to nausea.
- One patient withdrew from the study.
- Six patients also received azithromycin.
- By Day 6, nasopharyngeal (NP) PCRs were negative in 14 of 20 hydroxychloroquine-treated patients (70%) and two of 16 controls (12.5%).
- Among the hydroxychloroquine patients, eight of 14 patients (57.1%) who received only hydroxychloroquine and six of six patients (100%) who received hydroxychloroquine and azithromycin had negative NP PCRs by Day 6.
- Clinical outcomes for all patients were not reported for all patients.
- There are several methodologic concerns with this case series:
- The sample size of the series is small.
- The criteria for enrollment of cases and controls is unclear.
- Asymptomatic individuals were enrolled.
- Exclusion of six hydroxychloroquine patients includes one death and three ICU transfers.
- No clinical outcomes were reported; thus, the clinical significance of a negative PCR is unknown.
- The reason for the addition of azithromycin for some patients is unclear.
Methodologic problems with this case series limit the ability to draw conclusions regarding the efficacy of hydroxychloroquine with or without azithromycin.
Chloroquine and hydroxychloroquine have a similar toxicity profile, although hydroxychloroquine is better tolerated and has a lower incidence of toxicity than chloroquine.
Cardiac Adverse Effects:
- QTc prolongation, Torsade de Pointes, ventricular arrythmia, and cardiac deaths.
- The risk of QTc prolongation is greater for chloroquine than for hydroxychloroquine.
- Concomitant medications that pose a moderate to high risk for QTc prolongation (e.g., antiarrhythmics, antipsychotics, antifungals, macrolides [including azithromycin], fluoroquinolone antibiotics)12 should be used only if necessary. Consider using doxycycline rather than azithromycin as empiric therapy for atypical pneumonia.
- Baseline and follow-up ECGs are recommended when there are potential drug interactions with concomitant medications (e.g., azithromycin) or underlying cardiac diseases.13
- The risk-benefit ratio should be closely assessed for patients with cardiac disease, a history of ventricular arrhythmia, bradycardia (<50 beats per minute), or uncorrected hypokalemia and/or hypomagnesemia.
Other Adverse Effects:
- Hypoglycemia, rash, and nausea (divided doses may reduce nausea).
- Retinopathy, bone marrow suppression may occur with long-term use, but this is not likely with short-term use.
There is no evidence that glucose-6-phosphate dehydrogenase (G6PD) deficiency is relevant for the use of hydroxychloroquine, and G6PD testing is not recommended.
With chloroquine use, there is a greater risk for hemolysis in patients with G6PD deficiency. Conduct G6PD testing before initiating chloroquine. Consider using hydroxychloroquine until G6PD test results are available. If the test results indicate that the patient is G6PD deficient, hydroxychloroquine should be continued.
Chloroquine and hydroxychloroquine are moderate inhibitors of cytochrome P450 (CYP) 2D6, and these drugs are also P-glycoprotein (P-gp) inhibitors. Use caution when coadministering these drugs with medications that are metabolized by CYP2D6 (e.g., certain antipsychotics, beta-blockers, selective serotonin reuptake inhibitors, methadone) or transported by P-gp (e.g., certain direct-acting oral anticoagulants, digoxin).14
Considerations in Pregnancy
- Antirheumatic doses of chloroquine and hydroxychloroquine have been used safely in pregnant women with SLE.
- Hydroxychloroquine has not been associated with adverse pregnancy outcomes in ≥300 human pregnancies with exposure to the drug.
- A lower dose of chloroquine (500 mg once a week) is used for malaria prophylaxis in pregnancy.
- No dosing changes are necessary for chloroquine or hydroxychloroquine during pregnancy.
Considerations in Children
- Chloroquine and hydroxychloroquine have been used routinely in pediatric populations for the treatment and prevention of malaria and for rheumatologic conditions.
- Hydroxychloroquine is approved by the FDA for the treatment of malaria, lupus erythematosus, and rheumatoid arthritis and is available commercially. Hydroxychloroquine is not approved for the treatment of COVID-19.
- Chloroquine is not available commercially in the United States.
- 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.
- Food and Drug Administration. FDA cautions against use of hydroxychloroquine or chloroquine for COVID-19 outside of the hospital setting or a clinical trial due to risk of heart rhythm problems. 2020. Available at: https://www.fda.gov/drugs/drug-safety-and-availability/fda-cautions-against-use-hydroxychloroquine-or-chloroquine-covid-19-outside-hospital-setting-or. Accessed: May 8, 2020.
- Borba MGS, Val FFA, Sampaio VS, et al. 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 Netw Open. 2020;3(4):e208857. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32339248.
- Wang M, Cao R, Zhang L, et al. Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro. Cell Res. 2020;30(3):269-271. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32020029.
- Vincent MJ, Bergeron E, Benjannet S, et al. Chloroquine is a potent inhibitor of SARS coronavirus infection and spread. Virol J. 2005;2:69. Available at: https://www.ncbi.nlm.nih.gov/pubmed/16115318.
- Liu J, Cao R, Xu M, et al. Hydroxychloroquine, a less toxic derivative of chloroquine, is effective in inhibiting SARS-CoV-2 infection in vitro. Cell Discov. 2020;6:16. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32194981.
- Huang M, Tang T, Pang P, et al. Treating COVID-19 with chloroquine. J Mol Cell Biol. 2020;12(4):322-325. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32236562.
- Magagnoli J, Narendran S, Pereira F, et al. Outcomes of hydroxychloroquine usage in United States veterans hospitalized with COVID-19. medRxiv. 2020;[Preprint]. Available at: https://www.medrxiv.org/content/10.1101/2020.04.16.20065920v2.
- Tang W, Cao Z, Han M, et al. Hydroxychloroquine in patients with mainly mild to moderate coronavirus disease 2019: open label, randomised controlled trial. BMJ. 2020;369:m1849. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32409561.
- 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.
- Gautret P, Lagier JC, Parola P, et al. Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial. Int J Antimicrob Agents. 2020. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32205204.
- CredibleMeds. Combined list of drugs that prolong QT and/or cause torsades de pointes (TDP). 2020. Available at: https://crediblemeds.org/pdftemp/pdf/CombinedList.pdf. Accessed June 4, 2020.
- American College of Cardiology. Ventricular arrhythmia risk due to hydroxychloroquine-azithromycin treatment For COVID-19. 2020. Available at: https://www.acc.org/latest-in-cardiology/articles/2020/03/27/14/00/ventricular-arrhythmia-risk-due-to-hydroxychloroquine-azithromycin-treatment-for-covid-19. Accessed June 4, 2020.
- University of Liverpool. COVID-19 drug interactions. 2020. Available at: https://www.covid19-druginteractions.org/. Accessed April 8, 2020.