#Paxlovid #great #disillusionment
Nirmatrelvir was a beacon of hope for high-risk patients during the corona pandemic. But does the drug live up to its reputation? A new study raises doubts.
The protease inhibitor nirmarelvir has in combination with Ritonavir with the trade name Paxlovid® in the EU since January 28, 2022 Permit for therapy COVID-19 disease in adults who do not need oxygen therapy but are at increased risk of a severe course. Nirmatrelvir is a development of rupintrivir, an inhibitor of viral proteases that has been studied in clinical trials for the treatment of rhinovirus infections. It is administered in combination with ritonavir, also a protease inhibitor, which is also a strong inhibitor of the Cytochrom P450 3A4 (CYP3A4). Since protease inhibitors are metabolized by CYP3A4, ritonavir increases serum levels of nirmatrelvir through its inhibitory effect.
Great hope after approval study
Die Registration study recruited a total of 2,246 patients from July 2019 to December 9, 2021. Only patients who did not require additional oxygen and had at least one risk factor for severe COVID-19 were included. The risk factors included, among others Obesity (BMI > 25), age over 60 years, Type 1 diabetes mellitus and 2, immunosuppressive therapy, previous transplantation, cardiovascular disease, chronic Renal insufficiency and chronic lung diseases. Patients who were already against SARS-CoV-2 were vaccinated. In the study population, taking nirmatrelvir/ritonavir for 5 days significantly reduced hospitalization and death rates compared to placebo, from 6.5% to 0.7% when taken within 3 days of symptom onset became.
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These results were extremely promising, and the drug became a hope for the treatment of COVID-19 in Germany. But what about the effectiveness of Paxlovid® if there is no increased risk of a severe course of COVID-19? Furthermore, many people are now fully vaccinated against SARS-CoV-2 – so what about the effectiveness of Paxlovid in fully vaccinated people who are at high risk of becoming seriously ill with COVID-19?
Effect of risk and vaccination
These questions were addressed in a recent… New England Journal of Medicine published phase 2 to 3 double-blind, randomized, placebo-controlled Study examined. In the period from August 25, 2021 to July 25, 2022, a total of 1,296 patients suffering from COVID-19 were recruited. The participants were at least 18 years old, had a PCR-confirmed infection with SARS-CoV-2 and showed at least one symptom of COVID-19 disease within the last 5 days.
Only patients who either had no risk factors for a severe course of COVID-19 and were unvaccinated or patients who had risk factors for a severe course but were fully vaccinated against SARS-CoV-2 were included in the study. Patients were randomized 1:1 into two groups to receive either placebo or nirmatrelvir/ritonavir every 12 hours for 5 days. Participants completed an electronic symptom diary daily for 28 days. The primary endpoint of the study was time to sustained relief of all reported symptoms for COVID-19. Hospitalizations and deaths up to the 28th day after inclusion were also evaluated.
The great disillusionment
The results were sobering. The mean time to sustained relief of all symptoms was not significantly different between the two groups. Relief occurred after 12 days in therapy with nirmatrelvir/ritonavir and after 13 days in the placebo group. Reports of adverse events were also similar in both groups (25.8% with nirmatrelvir/ritonavir and 24.1% with placebo). Five participants (0.8%) in the nirmatrelvir/ritonavir group and 10 (1.6%) in the placebo group were hospitalized for COVID-19 or died from COVID-19 or other causes.
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The results of both studies indicate that a benefit of nirmatrelvir/ritonavir has so far only been found in unvaccinated patients with a risk factor for a severe course of COVID-19. But more and more people are fully immunized – be it through vaccinations or previous infections. If patients with risk factors are vaccinated, the risk of severe disease decreases and taking nirmatrelvir/ritonavir no longer appears to offer any benefit. The primary problem remains with immunocompromised patients who cannot be adequately protected despite vaccination. Taking Paxlovid® could be beneficial for this patient group.
Sources:
EMA: Paxlovid https://www.ema.europa.eu/en/documents/overview/paxlovid-epar-medicine-overview_en.pdf
J. Hammond, H. Leister-Tebbe, A. Gardner, P. Abreu, W. Bao et al: Oral Nirmatrelvir for High-Risk, Nonhospitalized Adults with Covid-19. N Engl J Med 2022;386:1397-1408. DOI: 10.1056/NEJMoa2118542
Hammond J, Fountaine RJ, Eunice C, Fleishaker D, Almas M, et al: Nirmatrelvir for Vaccinated or Unvaccinated Adult Outpatients with Covid-19. N Engl J Med 2024;390:1186-95. DOI: 10.1056/NEJMoa2309003.
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