Pan American Health Organization · 8 May 2020 rapid review
Rapid review of evidence on chloroquine/hydroxychloroquine for COVID-19 treatment up to 8 May 2020
- Issuer
- Pan American Health Organization
- Edition
- 8 May 2020 rapid review
- Audience
- Clinicians, public health professionals, national health authorities
- Evidence
- GRADE-rated evidence synthesis; critical appraisal of RCTs and observational studies
- Reviewed
- 19 Oct 2026 · GMJ
What this guideline says
GMJ summary
This rapid systematic review evaluates the efficacy and safety of chloroquine (CQ) and hydroxychloroquine (HCQ) for treating COVID-19, based on evidence available as of 8 May 2020. The review found lack of quality evidence to demonstrate that these drugs are effective in COVID-19 treatment. Evidence emerging from small studies with sub-optimal methodologies was conflicting and of very low certainty.
While some in vitro studies suggested antiviral activity against SARS-CoV-2, the in vivo clinical evidence consisted primarily of poorly designed randomised controlled trials and observational studies at high risk of bias. Critical methodological concerns included small sample sizes, inadequate randomisation, lack of blinding, selection bias, and residual confounding. Several studies reported potential cardiac adverse effects including QT interval prolongation and risk of torsade de pointes, particularly when hydroxychloroquine was combined with azithromycin.
PAHO urged national authorities to control the use of these medicines and prevent self-medication, warning that use outside of clinical trials may result in adverse effects including serious illness and death. The review emphasised the urgent need for well-designed randomised clinical trials to establish definitive evidence of benefits and harms before any recommendation could be made for clinical use.
Key points
For clinicians — doses and thresholds as stated in the guideline
- No high-quality evidence supports effectiveness of chloroquine or hydroxychloroquine in COVID-19 treatment as of May 2020
- Proposed dosing from early Chinese studies: chloroquine 500 mg twice daily for 10 days in mild, moderate and severe COVID-19 pneumonia
- Proposed hydroxychloroquine regimen: loading dose 400 mg twice daily, then maintenance 200 mg twice daily for 4 days
- French studies used hydroxychloroquine 600 mg daily for 6–10 days, often combined with azithromycin 500 mg day 1, then 250 mg daily for 4 days
- QT interval prolongation documented: 11–25% of patients developed QTc >500 ms (high risk for torsade de pointes)
- Combined hydroxychloroquine-azithromycin showed increased risk: cardiovascular mortality HR 2.19 (95% CI 1.22–3.94), heart failure HR 1.22 (95% CI 1.02–1.45)
- All published RCTs and observational studies rated as very low certainty evidence (GRADE) due to serious risk of bias and imprecision
- Use should be restricted to ethically approved randomised clinical trials with informed patient consent
GRADE certainty: hydroxychloroquine/chloroquine adverse events (all combined)
Table extracted from the guideline
| Outcome | Studies (design) | Risk of bias | Patients HCQ/CQ | Patients control | Relative risk (95% CI) | Absolute effect (95% CI) | Certainty |
|---|---|---|---|---|---|---|---|
| Adverse outcomes (all combined) | 4 randomised trials | Serious | 32/126 (25.4%) | 10/133 (7.5%) | RR 2.86 (1.51 to 5.45) | 140 more per 1,000 (from 38 more to 335 more) | ⨁⨁◯◯ LOW |
Source: Pan American Health Organization, COVID-19: Chloroquine and hydroxychloroquine research. Reproduced in summary form.
From the guideline
Verbatim
“There is a lack of quality evidence to demonstrate chloroquine and/or hydroxychloroquine are effective in the treatment of COVID-19.”
Editor’s perspective
Why this matters for Georgia and the region
Prof. Giorgi Pkhakadze, MD, MPH, PhD
Editor-in-Chief, Georgian Medical Journal · Chair, Public Health Institute of Georgia · WHO consultant, health and migration
This rigorous PAHO rapid review exemplifies the critical appraisal standards that should guide Georgia's response to therapeutic claims during health emergencies. As someone who has worked closely with WHO on evidence synthesis, I recognise the review's disciplined application of GRADE methodology to expose the profound weaknesses in the early COVID-19 literature—small samples, absent randomisation, uncontrolled confounding—that rendered estimates of effect unreliable. For Georgian clinicians, the cardiac safety signals are especially important: our National Center for Disease Control data show high prevalence of cardiovascular comorbidity, and the documented QT prolongation risk (11–25% reaching危險 thresholds) with hydroxychloroquine, compounded by azithromycin co-administration, posed real danger. The review's insistence on restricting use to ethically approved trials, rather than compassionate or emergency use based on hope, remains a lesson for our national protocols. One implementation reality for Georgia: even when international guidelines later evolved, our pharmacy supply chains and over-the-counter availability created persistent challenges in controlling access, underscoring the review's prescient call for national regulatory measures.
ORCID 0000-0001-7609-4515 · Perspective written for the GMJ Guidelines Library, 19 Oct 2026
Applicability
Georgia and the South Caucasus
This historical review documents the state of evidence during the early COVID-19 pandemic when Georgia, like other countries in the South Caucasus and Eastern Europe, faced urgent treatment decisions with limited evidence. The document’s rigorous methodology in critically appraising weak evidence and cautioning against premature adoption remains highly relevant for the region’s approach to emerging infectious diseases. National programmes in Georgia and neighbouring countries should note the review’s emphasis on: controlling access to prevent self-medication (chloroquine/hydroxychloroquine were available over-the-counter in some settings), prioritising resources for evidence-based interventions, the critical importance of cardiovascular monitoring when investigational treatments are used, and requiring robust randomised controlled trial evidence before incorporating new treatments into protocols. The cardiovascular safety concerns are particularly pertinent given the prevalence of cardiac comorbidities in the region’s ageing populations.
Questions this guideline answers
Quick answers
Was chloroquine or hydroxychloroquine proven effective for COVID-19 treatment?
No. As of May 2020, there was lack of quality evidence to demonstrate effectiveness. All available studies were small, poorly designed, and rated as very low certainty evidence. The body of evidence was conflicting and plagued by serious methodological flaws including inadequate randomisation, selection bias, and residual confounding.
What were the main safety concerns with hydroxychloroquine for COVID-19?
Cardiac toxicity was the primary concern. QT interval prolongation occurred in 11–25% of patients, with QTc exceeding 500 ms (high risk for lethal torsade de pointes arrhythmia) in many cases. When combined with azithromycin, there was increased risk of cardiovascular mortality (HR 2.19), heart failure (HR 1.22), and ventricular arrhythmias. One patient required emergent cardioversion for torsade de pointes.
What dosing regimens were studied in the early COVID-19 trials?
Chloroquine: 500 mg twice daily for 10 days (Chinese studies). Hydroxychloroquine: loading dose 400 mg twice daily on day 1, then 200 mg twice daily for 4 days (based on pharmacokinetic modelling); or 600 mg daily for 6–10 days (French studies). When combined with azithromycin: 500 mg on day 1, then 250 mg daily for 4 days. All regimens were investigational and not validated.
Should these drugs be used outside clinical trials?
No. PAHO strongly urged that use be restricted to ethically approved randomised clinical trials with informed patient consent. National authorities were advised to control access and prevent self-medication. Use outside trials may result in adverse effects including serious illness and death, and divert supplies from patients with proven indications (malaria, rheumatoid arthritis, lupus).
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- Issuer
- Pan American Health Organization
- Type
- Procedures, manuals, guidelines
- Edition
- 8 May 2020 rapid review
- Status
- Current
- Published
- 2020-01-01
- Languages
- English, Spanish (summary)
- Scope
- Rapid systematic review of chloroquine and hydroxychloroquine efficacy and safety in COVID-19
- Audience
- Clinicians, public health professionals, national health authorities
- Licence
- CC BY-NC-SA 3.0 IGO
- Evidence
- GRADE-rated evidence synthesis; critical appraisal of RCTs and observational studies
- Record history
- Created 19 Oct 2026 · updated 19 Oct 2026 · next check Apr 2027
Pan American Health Organization. COVID-19: Chloroquine and hydroxychloroquine research. Rapid review – 8 May 2020. Washington, D.C.: PAHO; 2020. Licence: CC BY-NC-SA 3.0 IGO.GMJ Guidelines Library records are original summaries written by the GMJ editorial team from the issuer’s published document and reviewed by a physician. They do not replace the full guideline. The document is the copyright of its issuer and is linked, not hosted. Spotted an error or a newer edition? Tell the Guidelines Desk.
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