Subject(s)
Antiviral Agents , COVID-19 Drug Treatment , Lactams , Leucine , Nitriles , Proline , Ritonavir , Viral Load , Antiviral Agents/adverse effects , Antiviral Agents/pharmacology , Antiviral Agents/therapeutic use , Drug Combinations , Humans , Lactams/adverse effects , Lactams/pharmacology , Lactams/therapeutic use , Leucine/adverse effects , Leucine/pharmacology , Leucine/therapeutic use , Nitriles/adverse effects , Nitriles/pharmacology , Nitriles/therapeutic use , Proline/adverse effects , Proline/pharmacology , Proline/therapeutic use , Recurrence , Ritonavir/adverse effects , Ritonavir/pharmacology , Ritonavir/therapeutic use , Viral Load/drug effectsSubject(s)
Antiviral Agents , COVID-19 Drug Treatment , Lactams , Leucine , Nitriles , Proline , Ritonavir , Antiviral Agents/adverse effects , Antiviral Agents/therapeutic use , Drug Combinations , Humans , Lactams/adverse effects , Lactams/therapeutic use , Leucine/adverse effects , Leucine/therapeutic use , Nitriles/adverse effects , Nitriles/therapeutic use , Proline/adverse effects , Proline/therapeutic use , Recurrence , Ritonavir/adverse effects , Ritonavir/therapeutic use , SARS-CoV-2ABSTRACT
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 useABSTRACT
INTRODUCTION: As coronavirus disease 2019 (COVID-19) outbreak globally, repurposing approved drugs is emerging as important therapeutic options. Danoprevir boosted by ritonavir (Ganovo) is a potent hepatitis C virus (HCV) protease (NS3/4A) inhibitor, which was approved and marketed in China since 2018 to treat chronic hepatitis C patients. METHODS: This is an open-label, single arm study evaluating the effects of danoprevir boosted by ritonavir on treatment naïve and experienced COVID-19 patients for the first time. Patients received danoprevir boosted by ritonavir (100âmg/100âmg, twice per day). The primary endpoint was the rate of composite adverse outcomes and efficacy was also evaluated. RESULTS: The data showed that danoprevir boosted by ritonavir is safe and well tolerated in all patients. No patient had composite adverse outcomes during this study. After initiation of danoprevir/ritonavir treatment, the first negative reverse real-time PCR (RT-PCR) test occurred at a median of 2 days, ranging from 1 to 8 days, and the obvious absorption in CT scans occurred at a median 3 days, ranging from 2 to 4 days. After 4 to 12-day treatment of danoprevir boosted by ritonavir, all enrolled 11 patients were discharged from the hospital. CONCLUSION: Our findings suggest that repurposing danoprevir for COVID-19 is a promising therapeutic option.