ABSTRACT
BACKGROUND: Nirmatrelvir is an orally administered severe acute respiratory syndrome coronavirus 2 main protease (Mpro) inhibitor with potent pan-human-coronavirus activity in vitro. METHODS: We conducted a phase 2-3 double-blind, randomized, controlled trial in which symptomatic, unvaccinated, nonhospitalized adults at high risk for progression to severe coronavirus disease 2019 (Covid-19) were assigned in a 1:1 ratio to receive either 300 mg of nirmatrelvir plus 100 mg of ritonavir (a pharmacokinetic enhancer) or placebo every 12 hours for 5 days. Covid-19-related hospitalization or death from any cause through day 28, viral load, and safety were evaluated. RESULTS: A total of 2246 patients underwent randomization; 1120 patients received nirmatrelvir plus ritonavir (nirmatrelvir group) and 1126 received placebo (placebo group). In the planned interim analysis of patients treated within 3 days after symptom onset (modified intention-to treat population, comprising 774 of the 1361 patients in the full analysis population), the incidence of Covid-19-related hospitalization or death by day 28 was lower in the nirmatrelvir group than in the placebo group by 6.32 percentage points (95% confidence interval [CI], -9.04 to -3.59; P<0.001; relative risk reduction, 89.1%); the incidence was 0.77% (3 of 389 patients) in the nirmatrelvir group, with 0 deaths, as compared with 7.01% (27 of 385 patients) in the placebo group, with 7 deaths. Efficacy was maintained in the final analysis involving the 1379 patients in the modified intention-to-treat population, with a difference of -5.81 percentage points (95% CI, -7.78 to -3.84; P<0.001; relative risk reduction, 88.9%). All 13 deaths occurred in the placebo group. The viral load was lower with nirmatrelvir plus ritonavir than with placebo at day 5 of treatment, with an adjusted mean difference of -0.868 log10 copies per milliliter when treatment was initiated within 3 days after the onset of symptoms. The incidence of adverse events that emerged during the treatment period was similar in the two groups (any adverse event, 22.6% with nirmatrelvir plus ritonavir vs. 23.9% with placebo; serious adverse events, 1.6% vs. 6.6%; and adverse events leading to discontinuation of the drugs or placebo, 2.1% vs. 4.2%). Dysgeusia (5.6% vs. 0.3%) and diarrhea (3.1% vs. 1.6%) occurred more frequently with nirmatrelvir plus ritonavir than with placebo. CONCLUSIONS: Treatment of symptomatic Covid-19 with nirmatrelvir plus ritonavir resulted in a risk of progression to severe Covid-19 that was 89% lower than the risk with placebo, without evident safety concerns. (Supported by Pfizer; ClinicalTrials.gov number, NCT04960202.).
Subject(s)
Antiviral Agents , COVID-19 Drug Treatment , Lactams , Leucine , Nitriles , Proline , Ritonavir , Administration, Oral , Adult , Antiviral Agents/administration & dosage , Antiviral Agents/adverse effects , Antiviral Agents/therapeutic use , Disease Progression , Double-Blind Method , Hospitalization , Humans , Lactams/administration & dosage , Lactams/adverse effects , Lactams/therapeutic use , Leucine/administration & dosage , Leucine/adverse effects , Leucine/therapeutic use , Nitriles/administration & dosage , Nitriles/adverse effects , Nitriles/therapeutic use , Proline/administration & dosage , Proline/adverse effects , Proline/therapeutic use , Ritonavir/administration & dosage , Ritonavir/adverse effects , Ritonavir/therapeutic use , SARS-CoV-2 , Treatment Outcome , Vaccination , Viral Load/drug effects , Viral Protease Inhibitors/administration & dosage , Viral Protease Inhibitors/adverse effects , Viral Protease Inhibitors/therapeutic useSubject(s)
COVID-19 Drug Treatment , Lactams/therapeutic use , Leucine/therapeutic use , Nitriles/therapeutic use , Proline/therapeutic use , Ritonavir/adverse effects , Ritonavir/therapeutic use , Viral Protease Inhibitors , Drug Interactions , Drug Therapy, Combination , Humans , Ritonavir/pharmacokinetics , Ritonavir/pharmacology , Viral Protease Inhibitors/adverse effects , Viral Protease Inhibitors/pharmacokinetics , Viral Protease Inhibitors/therapeutic useABSTRACT
We aimed to describe liver injury and identify the risk factors of liver injury in coronavirus disease (COVID-19) patients without chronic liver diseases (CLD). The clinical data of 228 confirmed COVID-19 patients without CLD were retrospectively collected from ten hospitals in Jiangsu, China. Sixty-seven (29.4%) of 228 patients without CLD showed abnormal liver function on admission, including increased alanine aminotransferase (ALT) (25 [11.0%]) U/L, aspartate aminotransferase (AST) 30 [13.2%]) U/L, gamma-glutamyl transferase (GGT) 28 [12.4%]) U/L, total bilirubin (Tbil) 16 [7.0%] µmol/L, and alkaline phosphatase (ALP) 10 [4.5%]) U/L. During hospitalization, 129 (56.3%) of 228 patients showed abnormal liver function, including elevated ALT (84 [36.8%]), AST (58 [25.4%]), GGT (67 [29.5%]), and Tbil (59 [25.9%]). Age over 50 years (odds ratio [OR], 2.086; 95% confidence interval [CI], 1.030-4.225; p = .041), male sex (OR, 2.737; 95% CI, 1.418-5.284; p = .003), and lopinavir-ritonavir (OR, 2.504; 95% CI, 1.187-5.283; p = .016) were associated with higher risk of liver function abnormality, while the atomized inhalation of interferon α-2b (OR, 0.256; 95% CI 0.126-0.520; p < .001) was associated with reduced risk of liver function abnormality during hospitalization. Mild to moderate liver injury was common in COVID-19 patients in Jiangsu, China. Age over 50 years, male sex, and lopinavir-ritonavir were the independent risk factors of liver impairment in COVID-19 patients during hospitalization.