Systematic Review Highlights Hydroxychloroquine Ambiguities


Investigators sought to summarize evidence about the benefits and harms of hydroxychloroquine and chloroquine as treatments or prophylaxis of COVID-19.

In laboratory experiments, hydroxychloroquine and chloroquine have shown antiviral effects against SARS-CoV-2. However, the clinical literature which has emerged from use among real patients with coronavirus disease 2019 (COVID-19) has been far more ambiguous.

A recent review, published in Annals of Internal Medicine by a team of investigators supported by the Agency for Healthcare Research and Quality, sought to summarize evidence about the benefits and harms of hydroxychloroquine and chloroquine as treatments or prophylaxis of COVID-19. The study team ultimately concluded that evidence on the benefits and harms of using hydroxychloroquine or chloroquine to treat COVID-19 is very weak and conflicting, alongside a lack of empirical study on use as prophylaxis.

The study team was guided by a series of questions with clinical relevance to COVID-19 treatment:

1. Is hydroxychloroquine or chloroquine effective at treating, in any setting, children or adults with COVID-19 infections?

2. Is hydroxychloroquine or chloroquine effective at preventing SARS-CoV-2 infections or COVID-19 in children or adults?

3. What are the potential harms and adverse events associated with use of hydroxychloroquine or chloroquine for treatment or prevention of COVID-19 infection?

Data from December 1, 2019 until May 8, 2020 were gathered via PubMed, Cochrane Library, EMBASE, Scopus, preprints,, the World Health Organization International Clinical Trials Registry Platform, bioRxiv, and the Chinese Clinical Trials Registry.

Selection criteria for studies included articles in any language reporting efficacy or safety outcomes from the 2 drugs in question, in any setting, in adults or in children with either suspected COVID-19 or risk for SARS-CoV-2 infection. Several investigators performed independent data extraction and quality assessments.

Ultimately, 4 randomized controlled trials, 9 case series, and 10 cohort studies were identified for hydroxychloroquine treatment analysis. There were no studies available evaluating prophylaxis.

“Evidence was conflicting and insufficient regarding the effect of hydroxychloroquine on such outcomes as all-cause mortality, progression to severe disease, clinical symptoms, and upper respiratory virologic clearance with antigen testing,” study authors wrote.

Several articles from the review found that some patients receiving hydroxychloroquine developed a QTc interval of 500 or greater, though the proportion of patients with adverse effects varied.

There were 2 studies on the efficacy of chloroquine. There was a trial, which compared higher-dose (600 mg twice daily for 10 days) with lower-dose (450 mg twice daily on day 1 and once daily for 4 days) therapy. The trial was halted due to concerns that the higher dose therapy may have been increasing lethality and QTc interval prolongation.

The other chloroquine efficacy data were from an observational study. The study compared adults with COVID-19 receiving chloroquine phosphate 500 mg once or twice daily with patients not receiving chloroquine. The results indicated minor benefit in fever resolution and virologic clearance.

The 2 drugs have been subject to immense media attention, both positive and negative. But for clinicians, the science has likely not been settled enough to motivate massive uptake of the controversial antimalarial drugs.

There were few controlled studies, and control for confounding was inadequate in observational studies,” authors cautioned.

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