Hepatotoxicity Of Remdesivir For Covid-19: Systematic Review And Meta-Analysis

INTRODUCTION: Remdesivir is a nucleotide analogue drug that inhibits RNA polymerases. It is a broad-spectrum antiviral drug that has been shown to inhibit COVID-19. The gastrointestinal side effects of remdesivir, especially hepatotoxicity, are concerning but unknown. Our study was aim to evaluate the hepatotoxicity of Remdesivir for COVID-19. METHODS: MEDLINE, the Cochrane Library and EMBASE were searched up to 6/1/2020. The following keywords were used in combination: Remdesivir, COVID-19 or SARS-CoV-2. Observational studies and clinical trials that utilized remdesivir for 5 day or 10 days among laboratory-confirmed COVID-19 and radiologically confirmed pneumonia patients were included. Given low incidences of side effects, studies that enrolled less than 100 patients were excluded. RESULTS: Total 396 literatures were searched and three clinical trials with 1,697 patients were included. Patients were aged more than 18 years old with median or mean age more than 55 in three studies. 63% were male. The pooled incidence rate for bilirubin elevation was 4% (95% confidence interval, 95% CI 1%–26%, I2 94.6%). The rate for grade 3 or 4 bilirubin elevation was 1% (95% CI 0–2%, I2 0.0%). There is no significant difference on the change of bilirubin between the remdesivir group and placebo group with pooled Odd Ratio (OR) of 0.96 (95% CI 0.48–1.94, I2 0.0%). The rate for AST and ALT elevation were 4% (95% CI 3%–7%, I2 59.6%) and 3% (95% CI 1%–13%, I2 91.8%) respectively. The reported rates for grade 3 or 4 AST elevation were 0% (95% CI 0–2%) by Wang et. and 3% (95% CI 2%–5%) by Goldman et. There is no significant difference on the change of AST between the remdesivir group and placebo group with pooled Odd Ratio (OR) of 0.60 (95% CI 0.34–1.06, I2 21.5%). The pooled rate for hypoalbuminemia was 13% (95% CI 9%–20%, I2 95.8%). The OR for hypoalbuminemia was 0.80 (95% CI 0.41–1.58, I2 0.0%). No acute liver failure was reported in all included studies. The reported rates of hepatotoxicity leading to drug discontinuation was 1% by Wang et. CONCLUSION: The incidence of hepatotoxicity of remdesivir is not as high as previous studies reported, which were mostly transient and tolerable during the remdesivir treatment. The elevation of liver enzymes could be associated with underlying COVID related hepatal injury. However, more quality studies are needed to confirm the safety of the remdesivir.Figure 1.: Pooled rates for liver function abnormalities of remdesivir.Figure 2.: Pooled Odd ratios for liver function abnormalities compared remdesivir with placebo.