Nirmatrelvir-ritonavir for COVID-19.
Ontology highlight
ABSTRACT:
SUBMITTER: McDonald EG
PROVIDER: S-EPMC8900806 | biostudies-literature | 2022 Feb
REPOSITORIES: biostudies-literature
Publications
Nirmatrelvir-ritonavir for COVID-19.
McDonald Emily G EG Lee Todd C TC
CMAJ : Canadian Medical Association journal = journal de l'Association medicale canadienne 20220203 6
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| S-EPMC10688265 | biostudies-literature
Project description:BackgroundNirmatrelvir-ritonavir has been authorized for emergency use by many countries for the treatment of coronavirus disease 2019 (Covid-19). However, the supply falls short of the global demand, which creates a need for more options. VV116 is an oral antiviral agent with potent activity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).MethodsWe conducted a phase 3, noninferiority, observer-blinded, randomized trial during the outbreak caused by the B.1.1.529 (omicron) variant of SARS-CoV-2. Symptomatic adults with mild-to-moderate Covid-19 with a high risk of progression were assigned to receive a 5-day course of either VV116 or nirmatrelvir-ritonavir. The primary end point was the time to sustained clinical recovery through day 28. Sustained clinical recovery was defined as the alleviation of all Covid-19-related target symptoms to a total score of 0 or 1 for the sum of each symptom (on a scale from 0 to 3, with higher scores indicating greater severity; total scores on the 11-item scale range from 0 to 33) for 2 consecutive days. A lower boundary of the two-sided 95% confidence interval for the hazard ratio of more than 0.8 was considered to indicate noninferiority (with a hazard ratio of >1 indicating a shorter time to sustained clinical recovery with VV116 than with nirmatrelvir-ritonavir).ResultsA total of 822 participants underwent randomization, and 771 received VV116 (384 participants) or nirmatrelvir-ritonavir (387 participants). The noninferiority of VV116 to nirmatrelvir-ritonavir with respect to the time to sustained clinical recovery was established in the primary analysis (hazard ratio, 1.17; 95% confidence interval [CI], 1.01 to 1.35) and was maintained in the final analysis (median, 4 days with VV116 and 5 days with nirmatrelvir-ritonavir; hazard ratio, 1.17; 95% CI, 1.02 to 1.36). In the final analysis, the time to sustained symptom resolution (score of 0 for each of the 11 Covid-19-related target symptoms for 2 consecutive days) and to a first negative SARS-CoV-2 test did not differ substantially between the two groups. No participants in either group had died or had had progression to severe Covid-19 by day 28. The incidence of adverse events was lower in the VV116 group than in the nirmatrelvir-ritonavir group (67.4% vs. 77.3%).ConclusionsAmong adults with mild-to-moderate Covid-19 who were at risk for progression, VV116 was noninferior to nirmatrelvir-ritonavir with respect to the time to sustained clinical recovery, with fewer safety concerns. (Funded by Vigonvita Life Sciences and others; ClinicalTrials.gov number, NCT05341609; Chinese Clinical Trial Registry number, ChiCTR2200057856.).
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Project description:We isolated a SARS-CoV-2 BA.2 variant from a person with COVID-19 recrudescence after nirmatrelvir/ritonavir treatment. Antiviral sensitivity and neutralizing antibody testing were performed with both parental SARS-CoV-2 and multiple variants of concern. We found that neither NM resistance nor absence of neutralizing immunity were likely causes of the recrudescence.
| S-EPMC9278181 | biostudies-literature
Project description:Nirmatrelvir/ritonavir (Paxlovid™) is an effective and safe antiviral drug that inhibits the main protease (Mpro), 3CL protease, of SARS-CoV-2. A reduction in COVID-19-related hospitalization or death was observed in patients treated with nirmatrelvir/ritonavir within five days of symptom onset. Moreover, good oral availability enables the usage of nirmatrelvir/ritonavir, not only in hospitalized patients, but also among outpatients. Nirmatrelvir (PF-07321332) has been demonstrated to stop the spread of COVID-19 in animal models. Despite frequent mutations in the viral genomes of SARS-CoV-2, nirmatrelvir shows an effective antiviral effect against recent coronavirus mutants. Despite the promising antiviral effect of nirmatrelvir, there are several unresolved concerns. First, the final results of large-scale clinical trials for early therapy of mild cases of COVID-19 are not yet published. Second, the effectiveness of nirmatrelvir against upcoming variants in the coming years requires close monitoring. Considering the promising preliminary results of the EPIC-HR trial, nirmatrelvir/ritonavir in conjunction with vaccines and non-pharmacological interventions, may represent the dawn in the dark of the COVID-19 pandemic.
| S-EPMC8868411 | biostudies-literature
Project description:ImportancePostmarket analysis of individuals who receive nirmatrelvir and ritonavir (Paxlovid [Pfizer]) is essential because they differ substantially from individuals included in published clinical trials.ObjectiveTo examine the association of nirmatrelvir and ritonavir with prevention of death or admission to hospital in individuals with different risks of complications from COVID-19 infection.Design, setting, and participantsThis is a cohort study of adult patients in British Columbia, Canada, between February 1, 2022, and February 3, 2023. Patients were eligible if they belonged to 1 of 4 higher-risk groups of individuals who received priority for COVID-19 vaccination. Two groups included clinically extremely vulnerable (CEV) people who were severely (CEV1) or moderately immunocompromised (CEV2). CEV3 individuals were not immunocompromised but had medical conditions associated with a high risk for complications from COVID-19. A fourth expanded eligibility (EXEL) group was added to allow wider access to nirmatrelvir and ritonavir for certain other higher-risk individuals who were not in a CEV group, such as those older than 70 years who were unvaccinated.ExposuresPatients with COVID-19 who received nirmatrelvir and ritonavir were matched to patients in the same vulnerability group; who were of the same sex, age, and propensity score for nirmatrelvir and ritonavir treatment; and who were also infected within 1 month of the individual treated with nirmatrelvir and ritonavir.Main outcomes and measuresThe primary outcome was death from any cause or emergency hospitalization with COVID-19 within 28 days.ResultsThere were 6866 individuals included in the study, of whom 3888 (56.6%) were female and whose median (IQR) age was 70 (57-80) years. Compared with unexposed controls, treatment with nirmatrelvir and ritonavir was associated with statistically significant relative reductions in the primary outcome in the CEV1 group (560 patients; risk difference [RD], -2.5%, 95% CI, -4.8% to -0.2%) and the CEV2 group (2628 patients; RD, -1.7%; 95% CI, -2.9% to -0.5%). In the CEV3 group, the RD was -1.3%, but the findings were not statistically significant (2100 patients; 95% CI, -2.8% to 0.1%). In the EXEL group, treatment was associated with higher risk of the outcome (RD, 1.0%), but the findings were not statistically significant (1578 patients; 95% CI, -0.9% to 2.9%).Conclusions and relevanceIn this cohort study of 6866 individuals in British Columbia, nirmatrelvir and ritonavir treatment was associated with reduced risk of COVID-19 hospitalization or death in CEV individuals, with the greatest benefit observed in severely immunocompromised individuals. No reduction in the primary outcome was observed in lower-risk individuals, including those aged 70 years or older without serious comorbidities.
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| S-EPMC9943556 | biostudies-literature
Project description:Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has emerged to cause pandemic respiratory disease in the past 2 years, leading to significant worldwide morbidity and mortality. At the beginning of the pandemic, only nonspecific treatments were available, but recently two oral antivirals have received emergency use authorization from the U.S. Food and Drug Administration for the treatment of mild to moderate coronavirus disease (COVID-19). Molnupiravir targets the viral polymerase and causes lethal mutations within the virus during replication. Nirmatrelvir targets SARS-CoV-2's main protease, and it is combined with ritonavir to delay its metabolism and allow nirmatrelvir to inhibit proteolytic cleavage of viral polyproteins during replication, preventing efficient virus production. Both drugs inhibit in vitro viral replication of all variants tested to date. Each is taken orally twice daily for 5 days. When started in the first 5 days of illness in persons at risk for complications due to COVID-19, molnupiravir and nirmatrelvir/ritonavir significantly decreased severe outcomes (hospitalizations and death) with adjusted relative risk reductions of 30% and 88%, respectively, for the two treatments. Molnupiravir should not be used in children or pregnant persons due to concerns about potential toxicity, and reliable contraception should be used in persons of childbearing potential. Nirmatrelvir/ritonavir may cause significant drug-to-drug interactions that limit its use in persons taking certain medications metabolized by certain cytochrome P450 enzymes. Both treatment regimens are important additions to the management of early COVID-19 in at-risk patients in the outpatient setting.
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