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Hydroxychloroquine

Last updated: October 1, 2020 

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The following is a curated review of key information and literature about this topic. It is not comprehensive of all data related to this subject.

Overview 

Hydroxychloroquine (HCQ) and chloroquine (CQ) are antimalarial agents that are also used to treat certain autoimmune disorders. HCQ has a lower incidence than CQ of adverse events with chronic use (Ben-Zvi, January 2011). Both drugs have immunomodulatory effects on various cytokines, including IL-1 and IL-6 (Ben-Zvi, January 2011), and prior to the COVID-19 pandemic were known to have in-vitro effects against various viruses, including SARS (Keyaerts, October 2004Vincent, August 2005Savarino, September 2011). Early in the course of the pandemic both agents were found to have in vitro activity against SARS-CoV-2 (Wang, February 2020Liu, March 2020Yao, March 2020). Given this potential biological plausibility, numerous clinical studies were initiated to examine the efficacy of these agents for treatment of COVID-19.   

In March 2020, the FDA issued an emergency use authorization for the use of HCQ/CQ in hospitalized patients with COVID-19. In April 2020, the FDA released a statement cautioning against use of HCQ or CQ for COVID-19 outside of the hospital setting or a clinical trial due to risk of heart rhythm problems. Based on subsequent clinical trial data showing a lack of efficacy and concern for safety signals, the FDA revoked the EUA in June 2020.  

Since the beginning of the pandemic there has been extensive research related to HCQ, including more than 5 various randomized controlled trials and several large observational cohort studies. Given the availability of higher-level data in the following review we have focused on these studies. Additional randomized controlled trial results are forthcoming.  

Guidelines 

Key Literature

In summary: While observational studies of the use of hydroxychloroquine (HCQ) and chloroquine (CQ) in patients with COVID-19 have had mixed results, several randomized controlled trials conducted in hospitalized patients with COVID-19 have not shown clinical benefit, nor have randomized controlled trials focused on post-exposure prophylaxis. In addition, some data suggest the use of HCQ may be associated with significant cardiac adverse events in patients with COVID-19. The use of HCQ or CQ is not recommended in patients with COVID-19.  

Retrospective cohort study of HCQ +/-azithromycin in patients hospitalized with COVID-19 (Arshad, July 2020). 

Study Population: 

  • 2,541 hospitalized COVID-19 patients in Michigan. 
  • Patients received HCQ + azithromycin (783 patients), HCQ alone (1202 patients), azithromycin alone (147 patients), or neither drug (409 patients). 
  • HCQ + azithromycin was given only to select patients with severe COVID-19 and minimal cardiac risk factors. 
  • Corticosteroid use varied by group: HCQ, 78.9%; HCQ + azithromycin, 74.3%; azithromycin, 38.8%; neither medication, 35.7%.  
  • Mechanical ventilation was required in 13% of HCQ alone arm, 29% among HCQ + azithromycin, and in 8% that did not receive either medication. 

Primary Endpoint: 

  • In-hospital mortality. 

Key Findings: 

  • Overall in-hospital mortality was 18.1% (45% in ICU patients). 
  • Mortality by treatment category was as follows: HCQ + azithromycin, 157/783 (20.1% [95% CI: 17.3%–23.0%]), HCQ alone, 162/1202 (13.5% [95% CI: 11.6%–15.5%]), azithromycin alone, 33/147 (22.4% [95% CI: 16.0%–30.1%]), neither drug, 108/409 (26.4% [95% CI: 22.2%–31.0%]). 
  • Compared to neither treatment, HCQ alone was associated with a 66% HR reduction (p < 0.001), while HCQ + azithromycin was associated with a HR reduction of 71% (p < 0.001). 
  • A matched propensity scoring of HCQ vs. no HCQ (190 patients in each group) showed that HCQ compared to no HCQ was associated with decreased mortality by a mortality HR decrease of 51% (p<0.009). 

Limitations: 

  • The retrospective nature of this study could have allowed for confounding. 
  • Determination of how treatment decisions were made is now well-described in the manuscript. 
  • Information on duration of symptoms prior to hospitalization is not available. 
  • There were substantial differences between the treatment arms with respect to corticosteroid use and their need for mechanical ventilation. 

Overall, in this retrospective cohort study, treatment with HCQ or HCQ + azithromycin was associated with reduction in COVID-19 associated mortality; however, the lack of balance between the groups and the lack of clarity around how treatment decisions were made limits the generalizability of these results.  

 

A Randomized Controlled Trial of HCQ for early treatment of patients with mild COVID-19 (Mitja, July 2020). 

Study population: 

  • 293 non-hospitalized patients with confirmed SARS-CoV-2 infection and fewer than 5 days of symptoms. 
  • 254 (86.7%) were health care workers. 
  • Patients were randomized to receive HCQ (157 patients) or no antiviral therapy (136).  

Primary endpoint: 

  • Reduction of viral RNA load in nasopharyngeal swabs up to 7 days after treatment start; patient disease progression using the WHO scale (WHO Working Group, August 2020) up to 28 days; time to complete resolution of symptoms.  

Results: 

  • No significant differences were found in the mean reduction of viral load in the control and HCQ arm at day 3 (-1.41 vs. -1.41 Log10 copies/mL [95% CI -0.28;0.29]), or at day 7 (-3.37 vs. -3.44; [-0.44;0.29]).  
  • There was no difference in risk of hospitalization between the control and intervention arms (7.1% vs. 5.9%; RR 0.75 [0.32;1.77]). 
  • There was no difference in the time to complete resolution of symptoms between the control and intervention arms (12 days vs. 10 days; p = 0.38). 

Limitations: 

  • There was no placebo group, which could have introduced confounding. 
  • Some patients also received protease inhibitors, which could have led to increased levels of HCQ. 
  • The overrepresentation of health care workers limits the generalizability of the findings.  
  • 60 patients were not included in the intention to treat analysis for various reasons, and 23 patients had a protocol deviation. 

Overall, in this randomized controlled trial of outpatients with early and mild COVID-19, the use of HCQ was not associated with a difference in reduction of viral load and set time points, a reduced risk of hospitalization, or a shortened time to symptom resolution. The results are limited by the lack of placebo and the lack of generalizability of the population.  

 

A Randomized Controlled Trial of HCQ in outpatients with early COVID-19 (Skipper, July 2020).  

Study population: 

  • 491 symptomatic, non-hospitalized adults with 4 days or less of symptoms and laboratory-confirmed COVID-19, probable COVID-19, or high-risk exposure within the preceding 14 days.  
  • 423 patients contributed to the primary endpoint: 241 (57%) health care workers, 106 (25%) household contacts, and 76 (18%) with other exposures. 
  • Patients were randomized to receive HCQ or placebo. 

Primary endpoint: 

  • Change in overall symptom severity over 14 days. 

Results: 

  • Change in symptom severity over 14 days did not differ between the HCQ and placebo groups (difference in symptom severity: absolute, −0.27 points; P = 0.117).  
  • At 14 days, 24% (49/201) of participants receiving HCQ had ongoing symptoms compared with 30% (59/ 194) receiving placebo (P = 0.21).  
  • Medication adverse effects occurred in 43% (92/ 212) of participants receiving HCQ versus 22% (46/211) receiving placebo (P < 0.001).  
  • There was no difference in hospitalization (10 in the placebo group vs 4 in the HCQ group; P = 0.29). 

Limitations: 

  • Participants were enrolled through internet-based surveys, which may have skewed the study population. 
  • The study population was heterogeneous. 
  • Only 58% of the sample were tested for SARS-CoV-2; it is possible not all the patients in the study had COVID-19. 

Overall, in this randomized controlled trial of outpatients with early COVID-19 disease, the use of HCQ was not associated with a change in symptom severity; adverse effects were common in the HCQ group compared to the placebo group. 

 

Randomized controlled trial of HCQ in patients with mild to moderate COVID-2019 (Tang, May 2020). 

Study Population: 

  • 150 hospitalized patients in China with laboratory confirmed COVID-19. 
  • Illness severity at admission was primarily mild (15%) or moderate (84%); 1% of cases were severe. 
  • 75 patients were randomized to receive HCQ + standard of care, and 75 were randomized to receive standard of care. Study arm assignment was not blinded.  
  • The dose of HCQ used was 1,200 mg daily for 3 days, followed by 800 mg daily for 2-3 weeks.  
  • In comparison, the most-used regimen in the United States is 800 mg on the first day followed by 400 mg daily for four days. 
  • The mean duration from symptom onset to randomization was 16.6 days. 

Primary endpoint: 

  • Viral clearance by 28 days. 
  • Secondary endpoint: rate of improvement in symptoms over 1 month (defined as defervescence, improved oxygen saturation and disappearance of respiratory symptoms). 

Key Findings: 

  • The probability of negative conversion by 28 days in the standard of care + HCQ group was 85.4% (95% CI 73.8% to 93.8%), similar to that in the SOC group (81.3%, CI  71.2% to 89.6%). 
  • Adverse events were reported in 21/70 (30%) HCQ recipients vs. 7/80 (9%) individuals not receiving HCQ.   

Limitations: 

  • Blinding was not utilized during assignment to the study arms; selection bias is possible. 
  • The study was terminated early due to low enrollment and the impression of benefit (which may have led to under-powering).  
  • The time between symptom onset and randomization was 16.6 days; patients may have been too far along in the course of their illness to derive a beneficial anti-viral effect.  

Overall, in this randomized controlled trial that was halted early due to low enrollment, HCQ had no effect on the duration of viral detection, despite the use of high doses and a prolonged 2-3 duration. 

 

A multicenter, open-label, randomized, placebo-controlled trial evaluated patients with mild-to-moderate COVID-19 (Cavalcanti, July 2020). 

Study population:  

  • 504 hospitalized patients with confirmed mild-to-moderate COVID-19 were randomized to receive either standard of care, HCQ + standard of care, or HCQ + Azithromycin + standard of care.  
  • There were 173 pts in the control group, 159 pts in the HCQ group, 172 pts in the HCQ + azithromycin group. 
  • The median time from symptom onset to randomization was 7 days.  

Primary endpoint:  

  • Clinical status at 15 days using a seven-level ordinal scale.  

Key findings: 

  • Compared to standard care, the proportional odds of having a worse score on the ordinal scale at 15 days was not affected by either HCQ (OR 1.21; P=1.00) or HCQ + azithromycin (OR 0.99; P=1.00). 
  • Compared to standard of care, more adverse events were reported in patients that received HCQ + azithromycin (39.3%) or HCQ alone (33.7%). 
  • QTc interval prolongation and liver enzyme elevations most common. 

Limitations:  

  • The median time of symptom onset to randomization was 7 days, which limits the generalizability of these results.   
  • Blinding was not employed during randomization, which could have introduced several levels of bias. 
  • A good number of patients had already received HCQ and/or azithromycin prior to study entry, which could have affected the results.  

Overall, in this open-label randomized clinical trial, in patients hospitalized with mild-to-moderate COVID-19, HCQ +/- azithromycin did not improve clinical status at 15 days compared to SOC.  Higher adverse events occurred in the patients who received HCQ +/- azithromycin. 

 

RECOVERY, a controlled, open-label trial comparing a range of possible treatments in patients hospitalized with COVID-19 (Holby, July 2020). 

Study population:  

  • 1561 patients were randomized to receive HCQ; 3155 patients were randomized to standard of care. 

Primary endpoint:  

  • 28-day mortality. 

Key findings: 

  • 28-day mortality did not differ in those patients that received HCQ vs. usual care (26.8% vs. 25.0% rate ratio 1.09; 95% CI 0.96 to 1.23). 
  • Patients allocated to HCQ were less likely to be discharged from hospital alive within 28 days (60.3% vs. 62.8%; rate ratio 0.92; 95% CI 0.85-0.99). 
  • Patients allocated to HCQ and not on invasive mechanical ventilation at baseline were more likely to reach the composite endpoint of invasive mechanical ventilation or death (29.8% vs. 26.5%; risk ratio 1.12; 95% CI 1.01-1.25). 

Limitations: 

  • The mortality rate of patients with severe COVID-19 disease found in this study is higher than what has been generally found in this group in the United States. 
  • Open-label design; researchers and patients in the study knew who was receiving which treatment. This could have introduced bias into the results. 
  • Not all patients had proven SARS-CoV-2 infection via RT-PCR, but in post-hoc analysis of patients with a positive PCR result (90% of the sample), the results were similar.  

Overall, in this randomized controlled open-label trial of patients hospitalized with COVID-19, HCQ was not associated with 28-day mortality reduction, but was associated with an increased length of hospital stay and increased risk of progressing to invasive mechanical ventilation or death. 

 

Prospective Observational Study of HCQ in Hospitalized Patients with COVID-19 (Geleris, May 2020). 

Study Population: 

  • 1376 non-intubated patients hospitalized with COVID-19 at a single institution in New York City. 
  • 811 (58.9%) received HCQ; 45.8% were treated within 24 hours and 85.9% within 48 hours. 

Primary endpoint:  

  • Composite of intubation or death in a time-to-event analysis. 

Key findings: 

  • There was no significant association between HCQ use and intubation or death (HR 1.04, 95% CI 0.82-1.32). 

Limitations: 

  • This is an observational study; therefore, confounding is possible. 
  • The decision to administer HCQ was made by the treating physician; selection bias may have occurred. 
  • The study occurred at a single institution; therefore, results may not be generalizable. 

Overall, in this prospective observational study of patients hospitalized with COVID-19, HCQ was not associated with an increase or reduction in the composite endpoint of death or intubation. 

 

Randomized controlled trial of HCQ in patients with COVID-19 (Chen, April 2020).

Study Population: 

  • 62 hospitalized patients with non-severe COVID-19.  
  • 31 patients were randomized to receive 5 days of HCQ, and 31 to receive standard of care. 
  • Standard of care included antiviral agents, antibacterial agents and immunoglobulin with or without corticosteroids. 

Primary Endpoint: 

  • Time to clinical recovery (defined as becoming afebrile and cough relief for 72 hours or more), clinical characteristics and changes in chest CT. 

Key Findings: 

  • Compared with the control group, body temperature recovery time was significantly shortened in the HCQ treatment group (2.2 ± 0.4d vs 3.2 ± 1.3d). 
  • Cough duration was shorter in the HCQ group compared to the control group (2.0 ± 0.2d vs 3.1 ± 1.5d). 
  • More patients had radiographic improvement with HCQ [25/31 (81%) vs 17/31 (55%), p=0.05]. 

Limitations: 

  • No baseline characteristics of patients were provided. 
  • The end point focused on resolution of fever and cough; the clinical relevance of this endpoint is not clear.  
  • At entry into the study, in the HCQ arm 9 patients had no fever and 9 had no cough. In the control arm 14 patients had no fever, and 16 had no cough. It is not clear how these patients were accounted for in the analysis.  
  • No information about viral load was included. 

Overall, in this randomized controlled trial of patients with mild COVID-19, HCQ was associated with a shorter time to clinical improvement (defined by resolution of fever and cough) and radiographic improvement. However, at study entry many patients had already met the time to clinical recovery study endpoints; it is not clear how the analysis accounted for these patients.   

 

Additional Literature

Hydroxychloroquine as pre-exposure prophylaxis for COVID-19 in healthcare workers: a randomized trial (Rajasingham, September 2020). In this randomized, double-blind, placebo-controlled trial of 1483 healthcare workers (of which 79% reported performing aerosol-generating procedures) who had ongoing exposure to persons with Covid-19, individuals were randomized to HCQ 400mg once weekly or twice weekly for 12 weeks, with the primary endpoint being confirmed or probable Covid-19-compatible illness. For once weekly HCQ prophylaxis, the hazard ratio was 0.72 (95% CI 0.44-1.16; P=0.18) and for twice weekly HCQ it was 0.74 (95% CI 0.46-1.19; P=0.22), compared with placebo.

Early Hydroxychloroquine but not Chloroquine use reduces ICU admission in COVID-19 patients (Lammers, September 2020)In this retrospective cohort study of 1064 hospitalized patients at 14 hospitals in the Netherlands, 566 patients received treatment with either HCQ (n = 189) or CQ (n = 377), and 498 patients received no treatment. In a multivariate propensity matched weighted competing regression analysis, there was no significant effect of (H)CQ on mortality. HCQ was associated with a significant decreased risk of transfer to the ICU (HR = 0.47, p = 0.008), when compared to controls.

Randomized Trial of HCQ as Post Exposure Prophylaxis for COVID-19 (Boulware, August 2020): In this randomized, double-blind, placebo-controlled trial of 821 persons with an either occupational or household high-reisk exposure to COVID-19, individuals were randomized within 4 days of exposure to receive either placebo or HCQ (800 mg once, followed by 600 mg in 6 to 8 hours, then 600 mg daily for 4 additional days). The incidence of new COVID-19 compatible illness did not differ significantly between those who received HCQ (49 of 414 [11.8%]) and those who received placebo (58 of 407 [14.3%]; absolute difference −2.4 percentage points; P=0.35). 

Retrospective Cohort Study of HCQ + Azithromycin in Hospitalized Patients with COVID-19 (Million, May 2020): 1061 hospitalized patients with COVID-19 who were treated with HCQ and azithromycin were analyzed. 95% of the patients had mild disease and were unlikely to progress. Within 10 days of treatment, good clinical outcome reported in 973 patients (91.7%) and poor clinical outcome reported in 46 patients (4.3%). Persistent nasal carriage of SARS-CoV-2 reported at completion of treatment in 47 patients (4.4%).  

Retrospective Cohort Study of In-Hospital Mortality and HCQ or Azithromycin in Patients with COVID-19 (Rosenberg, May 2020): Compared to no treatment with HCQ or azithromycin, the adjusted hazard ratio for in-hospital mortality for treatment with HCQ alone was 1.08, for azithromycin alone was 0.56, and for HCQ + azithromycin was 1.35. None of these hazard ratios were statistically significant. 

Safety

Across the body of evidence from several RCTs, treatment with HCQ may increase the risk of experiencing adverse events (Tang, May 2020Cavalcanti, July 2020). 

  • One RCT suggests increased risk of QT prolongation among patients treated with HCQ+AZ compared to those not receiving HCQ (RR: 8.50; 95% CI: 1.16-62.31) (Cavalcanti, July 2020). 

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