COVID-19 and Antimalarial Drugs: Harms Outweigh Benefits

Abstract and Introduction

Introduction

Coronavirus disease 2019 (COVID-19) was first associated with a cluster of pneumonia cases during December 2019 in Wuhan, China. After rapid spread of the disease across China and to several countries,^[1] the World Health Organization declared a global health emergency on January 30, 2020, followed by a global pandemic on March 11, 2020.

Coronaviruses are a large family of viruses that are widespread among birds and mammals and cause a variety of illnesses. The virus that causes COVID-19 is an enveloped single-strand RNA zoonotic virus associated with a severe respiratory syndrome.^[2] Spread occurs via human-to-human transmission primarily by inhalation of large respiratory droplets associated with coughing, sneezing, singing, or talking (these heavy droplets may travel 6 feet [1.8 m] or more but fall relatively quickly), or tiny aerosolized particles (< 5 μm in diameter) that are light and thus can stay suspended in the air for hours, especially in stagnant air. Less commonly, virus particles can be transmitted through contact with infected surfaces (fomites) or feces.^[1,3–6]

Following a short incubation (median 4–5 days),^[4] clinical features most often include fever, fatigue, dry cough, dyspnea, mild pneumonia, myalgia, and anorexia. Less common symptoms include sore throat, dizziness, headache, diarrhea, and other gastrointestinal symptoms.^[1,2,4,7,8] In an early report of more than 70 000 cases in China, most cases were mild (> 80%), but severe (14%) and critical (5%) cases required hospital admission and intensive care. Some patients' condition deteriorated rapidly within 1 week of illness onset.^[4] Severe cases were characterized by dyspnea, respiratory rate greater than 30/min, oxygen saturation less than 93%, and lung infiltrates exceeding 50% within 24 to 48 hours of illness onset; critical cases involved respiratory failure, sepsis, and/or multiple organ dysfunction. Mortality rates were estimated at 2.3% of confirmed cases.^[9] Major risk factors for severe disease and mortality include increasing age and various comorbidities (eg, hypertension, heart disease, prior stroke, diabetes, chronic lung and kidney disease, immunosuppression).^[1,2,4,8,10]

Absent a vaccine and effective treatment, research has been focused on developing COVID-19 diagnostic and antibody tests and on testing therapies such as remdesivir, convalescent plasma, and the antimalarial drugs chloroquine and hydroxychloroquine, which are also used for autoimmune diseases such as lupus erythematosus or rheumatoid arthritis. Given that little evidence is available on therapies for COVID-19, the PICO (patient problem, intervention, comparison, and outcome) question for this evidence synthesis was, Is chloroquine or hydroxychloroquine safe and effective in reducing the severity of COVID-19 symptoms and disease mortality?

Table 1. Randomized controlled trials on hydroxychloroquine for treatment of coronavirus disease 2019 (COVID-19)
Reference	Design (N, sample)	Main findings	Level of evidence
Rosenberg et al,¹¹ 2020	Retrospective multicenter cohort (N = 7914 patients with COVID-19 admitted to 25 hospitals) Patients treated with: Hydroxychloroquine alone Hydroxychloroquine with azithromycin Azithromycin alone Neither drug	Overall, in-hospital mortality 20.3% No significant difference in abnormal electrocardiographic findings between groups In adjusted analyses: No significant difference in mortality Hydroxychloroquine with azithromycin, 22.5% Hydroxychloroquine alone, 18.9% Azithromycin alone, 10.9% Neither drug, 17.8% Compared with no drug treatment, cardiac arrest was significantly more likely with hydroxychloroquine/azithromycin combination (but not hydroxychloroquine or azithromycin alone)	C
Chen et al,¹² 2020	Randomized controlled trial (N = 62 patients with COVID-19) Control vs experimental (5-day 400 mg hydroxychloroquine)	Hydroxychloroquine group: No progression to severe illness: 0% vs 13% in controls More pneumonia improvement: 81% vs 55% in controls Recovery significantly shortened: Fever remission: 2.2 days vs 3.2 days in controls Cough remission: 2.0 days vs 3.1 days in controls	C
Cortegiani et al,¹³ 2020	Systematic review (1 in vitro study, 23 ongoing clinical trials, 2 national guidelines, 1 expert consensus, 1 letter, 1 editorial)	Chloroquine highly effective in reducing viral replication (in vitro study); no data yet from ongoing trials Guidelines recommended: Initial chloroquine dose 600 mg followed by 300 mg after 12 hours on day 1, then 300 mg × 2 on days 2–5 (severe infections) or Chloroquine 500 mg × 2 or hydroxychloroquine 200 mg BID × 10 days Expert opinion recommended: Chloroquine 500 mg × 2 BID × 10 days (mild/moderate/severe COVID-19)	C
Tang et al,¹⁴ 2020	Randomized controlled trial (N = 150 admitted patients) Control vs experimental (hydroxychloroquine 1200-mg loading dose x 3 days followed by maintenance dose of 800 mg daily for 2 weeks (mild/moderate COVID) or 3 weeks (severe COVID); doses adjusted with adverse effects	Probability of negative conversion by day 28 similar between groups (85.4% hydroxychloroquine group vs 81.3% control group) (P > .05) Adverse effects in 30% of patients in hydroxychloroquine group (vs 9% in control group) Diarrhea most common 2 patients treated with hydroxychloroquine had serious adverse effects	C
Chowdhury et al,¹⁵ 2020	Systematic review (n = 7 completed trials and 29 registered clinical trials)	Of 7 trials, 5 had favorable outcomes with chloroquine/hydroxychloroquine treatment but 2 had no change Conclusions on efficacy and safety severely limited by poor study designs and various degrees of bias	C

Table 1. Randomized controlled trials on hydroxychloroquine for treatment of coronavirus disease 2019 (COVID-19)

Reference

Design (N, sample)

Main findings

Level of evidence

Rosenberg et al,¹¹ 2020

Retrospective multicenter cohort (N = 7914 patients with COVID-19 admitted to 25 hospitals)
Patients treated with:
   Hydroxychloroquine alone
   Hydroxychloroquine with azithromycin
   Azithromycin alone
   Neither drug

Overall, in-hospital mortality 20.3%
No significant difference in abnormal electrocardiographic findings between groups
In adjusted analyses:
   No significant difference in mortality
      Hydroxychloroquine with azithromycin, 22.5%
      Hydroxychloroquine alone, 18.9%
      Azithromycin alone, 10.9%
      Neither drug, 17.8%
Compared with no drug treatment, cardiac arrest was significantly more likely with hydroxychloroquine/azithromycin combination (but not hydroxychloroquine or azithromycin alone)

Chen et al,¹² 2020

Randomized controlled trial (N = 62 patients with COVID-19)
Control vs experimental (5-day 400 mg hydroxychloroquine)

Hydroxychloroquine group:
   No progression to severe illness: 0% vs 13% in controls
   More pneumonia improvement: 81% vs 55% in controls
   Recovery significantly shortened:
      Fever remission: 2.2 days vs 3.2 days in controls
      Cough remission: 2.0 days vs 3.1 days in controls

Cortegiani et al,¹³ 2020

Systematic review (1 in vitro study, 23 ongoing clinical trials, 2 national guidelines, 1 expert consensus, 1 letter, 1 editorial)

Chloroquine highly effective in reducing viral replication (in vitro study); no data yet from ongoing trials
Guidelines recommended:
   Initial chloroquine dose 600 mg followed by 300 mg after 12 hours on day 1, then 300 mg × 2 on days 2–5 (severe infections) or
   Chloroquine 500 mg × 2 or hydroxychloroquine 200 mg BID × 10 days
Expert opinion recommended:
   Chloroquine 500 mg × 2 BID × 10 days (mild/moderate/severe COVID-19)

Tang et al,¹⁴ 2020

Randomized controlled trial (N = 150 admitted patients)
Control vs experimental (hydroxychloroquine 1200-mg loading dose x 3 days followed by maintenance dose of 800 mg daily for 2 weeks (mild/moderate COVID) or 3 weeks (severe COVID); doses adjusted with adverse effects

Probability of negative conversion by day 28 similar between groups (85.4% hydroxychloroquine group vs 81.3% control group) (P > .05)
Adverse effects in 30% of patients in hydroxychloroquine group (vs 9% in control group)
Diarrhea most common
2 patients treated with hydroxychloroquine had serious adverse effects

Chowdhury et al,¹⁵ 2020

Systematic review (n = 7 completed trials and 29 registered clinical trials)

Of 7 trials, 5 had favorable outcomes with chloroquine/hydroxychloroquine treatment but 2 had no change
Conclusions on efficacy and safety severely limited by poor study designs and various degrees of bias

Level	Description
A	Meta-analysis or meta-synthesis of multiple controlled studies with results that consistently support a specific action, intervention, or treatment (systematic review of a randomized controlled trial)
B	Evidence from well-designed controlled studies, both randomized and nonrandomized, with results that consistently support a specific action, intervention, or treatment
C	Evidence from qualitative reviews, integrative reviews, or systematic reviews of qualitative, descriptive, or correlational studies or randomized controlled trials with inconsistent results
D	Evidence from peer-reviewed professional organizational standards, with clinical studies to support recommendations
E	Theory-based evidence from expert opinion or multiple case reports
M	Manufacturer's recommendation only

COVID-19 and Antimalarial Drugs

Abstract and Introduction

Introduction

Tables

Tables

References

Authors and Disclosures

Authors and Disclosures

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