Adverse effects of remdesivir, hydroxychloroquine, and lopinavir/ritonavir when used for COVID-19: systematic review and meta-analysis of randomized trials

Background: To summarize specific adverse effects of remdesivir, hydroxychloroquine, and lopinavir/ritonavir in patients with COVID-19.

Methods: We searched 32 databases through 27 October 2020. We included randomized trials comparing any of the drugs of interest to placebo or standard care, or against each other. We conducted fixed-effects pairwise meta-analysis and assessed the certainty of evidence using the GRADE approach.

Results: We included 16 randomized trials which enrolled 8226 patients. For most interventions and outcomes the certainty of the evidence was very low to low except for gastrointestinal adverse effects from hydroxychloroquine, which was moderate certainty. Compared to standard care or placebo, low certainty evidence suggests that remdesivir may not have an important effect on acute kidney injury or cognitive dysfunction/delirium. Low certainty evidence suggests that hydroxychloroquine may increase the risk of cardiac toxicity (and cognitive dysfunction/delirium, whereas moderate certainty evidence suggests hydroxychloroquine probably increases the risk of diarrhoea (RD 106 more per 1000, 95% CI: 48 more to 175 more) and nausea and/or vomiting (RD 62 more per 1000, 95% CI: 23 more to 110 more) compared to standard care or placebo. Low certainty evidence suggests lopinavir/ritonavir may increase the risk of diarrhoea and nausea and/or vomiting compared to standard care or placebo.

Discussion: Hydroxychloroquine probably increases the risk of diarrhoea and nausea and/or vomiting and may increase the risk of cardiac toxicity and cognitive dysfunction/delirium. Lopinavir/ritonavir may increase the risk of diarrhoea and nausea and/or vomiting. Remdesivir may have no important effect on risk of acute kidney injury or cognitive dysfunction/delirium. These findings provide important information to support the development of evidence-based management strategies for patients with COVID-19.

Funding: This study was supported by the Canadian Institutes of Health Research (grant: VR4-172738)

Registration: Not registered in PROSPERO, protocol available in the supplementary material of BMJ 2020;370:m2980; http://dx.doi.org/10.1136/bmj.m2980.