Resistance of SARS-CoV-2 to antivirals was shown to develop in immunocompromised individuals receiving remdesivir. We describe an immunocompromised patient who was treated with repeated and prolonged courses of nirmatrelvir and developed de-novo E166V/L50F mutations in the Mpro region. These mutations were associated with clinical and virological treatment failure.

This study aims to investigate the activity of the remdesivir-nirmatrelvir combination against Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) and to report a case of Coronavirus Disease 2019 (COVID-19) cured with this combination.
A Vero E6 cell-based infection assay was used to investigate the in vitro activity of the remdesivir-nirmatrelvir combination. The SARS-CoV-2 strains tested were 20A.EU1, BA.1 and BA.5. After incubation, a viability assay was performed. The supernatants were collected and used for viral titration. The Highest Single Agent (HSA) reference model was calculated. An HSA score >10 is considered synergic.
Remdesivir and nirmatrelvir showed synergistic activity at 48 and 72 h, with an HSA score of 52.8 and 28.6, respectively (p < 0.0001). These data were confirmed by performing supernatant titration and against the omicron variants: the combination reduced the viral titer better than the more active compound alone. An immunocompromised patient with prolonged and critical COVID-19 was successfully treated with remdesivir, nirmatrelvir/ritonavir, tixagevimab/cilgavimab and dexamethasone, with an excellent clinical-radiological response. However, she required further off-label prolonged therapy with nirmatrelvir/ritonavir until she tested negative.
Remdesivir-nirmatrelvir combination has synergic activity in vitro. This combination may have a role in immunosuppressed patients with severe COVID-19 and prolonged viral shedding.

Background Coronavirus disease 2019 (COVID-19) is an infectious disease that shortly progressed into an unprecedented pandemic spreading all over the world and causing millions of deaths. Many new COVID-19-specific therapies were suggested for the treatment of the patients at increased risk of progression to severe disease, especially those who were unvaccinated and those with a likely inadequate vaccine response. One of the preferred therapies in this setting is Paxlovid, a combination of the oral protease inhibitors nirmatrelvir and ritonavir. Paxlovid was authorized by the Saudi Ministry of Health for the treatment of mild to moderate COVID-19. This study aimed to report the effects of Paxlovid on the mortality of the COVID-19 patients at Dammam Medical Complex (DMC) and Qatif Complex Hospital (QCH), two hospitals in the Eastern Provence of Saudi Arabia, and compare the results with the international data. Methods The study was a retrospective study that included all the COVID-19 patients who were treated with Paxlovid at DMC and QCH between January and December 2022. Those patients were compared with control COVID-19 patients who did not receive Paxlovid. The patients were included irrespective of their COVID-19 vaccination status. All the patients were managed according to the Saudi Ministry of Health guidelines. They were followed up through the infectious disease virtual clinics and were monitored for ICU admissions and death of any cause for three months following their COVID-19 infections. Results A total of 92 COVID-19 patients were included. The patients consisted of 47 male and 45 female patients (51.09% and 48.91%, respectively). The mean ± standard deviation for the patients\' age was 55.58±19.25 years. Twenty-eight patients were given Paxlovid (30.43%). Eighteen patients (19.57%) died. The use of Paxlovid was associated with lower ICU admissions (0.0% vs. 18.75%, P value <0.05) and with lower deaths (3.57% vs 26.56%, P value <0.05) but the Paxlovid group included less immunocompromised patients (7.14% vs. 60.94%, P value <0.001), cancer patients (0.0% vs. 42.19%, P value <0.001), and chronic kidney disease patients (7.14% vs. 29.69%, P value <0.05) than the control group. Conclusion This study suggests that Paxlovid is highly effective in reducing the risk of severe COVID-19 or mortality. However, larger studies with better qualities are needed for a full assessment of the role of Paxlovid in COVID-19 management in Saudi Arabia.

In immunocompromised patients, persistent SARS-CoV-2 viral shedding and relapsing COVID-19 pneumonia have been described. Currently, little is known about the management of persisting COVID-19, and immunocompromised patients are recommended to be treated using antivirals and immunomodulatory therapies at similar doses and durations as the general population. Previous case reports have described treatment with repeated and prolonged courses of remdesivir and some evidence is emerging in the use of nirmatrelvir/ritonavir combination (NMV/r).
We describe a patient with recent chemotherapy including rituximab for follicular lymphoma with persisting SARS-CoV-2 infection. Polymerase chain reaction tests (PCR), cycle threshold values and blood SARS-CoV-2 antigen levels were evaluated.
The patient presented with persisting SARS-CoV-2 with relapsing COVID-19 pneumonia. The patient was treated successfully with repeated courses of NMV/r without any observed adverse effects. After the third, prolonged course, the patient remained afebrile and PCR negative, and no relapses have been observed four months after the third NMV/r course.
Nirmatrelvir-ritonavir could offer a more accessible alternative to remdesivir. Further research and guidelines for persisting SARS-CoV-2 infection in immunocompromised patients are urgently needed.

Nirmatrelvir is an antiviral drug with a novel mechanism of action, targeting the 3-CL protease, and is used in the treatment of COVID-19. However, the potential side effects have not yet been fully studied. The aim of this study was to identify potential safety signals of nirmatrelvir by analysing post-marketing safety data based on the largest publicly available worldwide pharmacovigilance database.
We analysed nirmatrelvir adverse events to identify and characterize relevant safety signals based on the FDA Adverse Event Reporting System database in 2022. The case/non-case approach was used to estimate the reporting odds ratio (ROR) and information component (IC) with relevant confidence intervals (95% CI) for adverse events (AEs) that numbered 4 or more.
A total of 26 846 cases were included. Disease recurrence (ROR [95% CI] = 413.2 [395.6-431.59]), dysgeusia (ROR [95% CI] = 110.84 [106.04-115.85]), anosmia (ROR [95% CI] = 15.21 [12.76-18.11]), ageusia (ROR [95% CI] = 9.80 [8.50-11.3]) and urticaria (ROR [95% CI] = 1.91 [1.69-2.17]) were the main safety signals. In addition, abdominal pain upper and skin toxicity were two specific safety signals of nirmatrelvir. In the pregnant population, there was a significant increased ROR for life-threatening conditions (ROR [95% CI] = 8.00 [1.77-36.20]).
Our study identified that the main and specific safety signals of nirmatrelvir were disease recurrence, dysgeusia, abdominal pain upper and skin toxicity. Clinicians and pharmacists should be vigilant of these AEs, although differentiating between COVID-19 symptoms and AEs can be challenging. Notably, a potential safety concern of nirmatrelvir should be a warning based on a small number of events in the pregnant population. However, the available data are insufficient, and further continued pharmacovigilance and surveillance is needed to fully understand this issue.

Nirmatrelvir/ritonavir association has been authorized for conditional use in the treatment of COVID-19, especially in solid-organ transplant recipients who did not respond to vaccine and are still at high risk of severe disease. This combination remains at risk of drug interactions with immunosuppressants, so monitoring drug levels seems necessary. After a simple protein precipitation of plasma sample, analytes were analyzed using an ultrahigh performance liquid chromatography system coupled with tandem mass spectrometry in a positive ionization mode. Validation procedures were based on the guidelines on bioanalytical methods issued by the European Medicine Agency. The analysis time was 4 min per run. The calibration curves were linear over the range from 10 to 1000 ng/mL for ritonavir and 40 to 4000 ng/mL for nirmatrelvir, with coefficients of correlation above 0.99 for all analytes. Intra-/interday imprecisions were below 10%. The analytical method also meets criteria of matrix effect, carryover, dilution integrity, and stability. In the context of a SARS-CoV-2 infection in a renal transplant recipient, we present a case of tacrolimus overdose with serious adverse events despite discontinuation of nirmatrelvir and ritonavir. The patient had still effective concentrations of nirmatrelvir and tacrolimus 4 days after drug discontinuation. This method was successfully applied for therapeutic drug monitoring in clinical practice.

Since the declaration of COVID-19 as a pandemic in 2020, several therapies have been developed to reduce symptoms of COVID-19 infection and prevent progression. Paxlovid is an antiviral that was authorized for emergency use in December 2021 for non-hospitalized symptomatic patients with COVID-19 to prevent progression to severe disease. Relapse of symptoms following a period of improvement after treatment with Paxlovid has been described recently. Data are limited, but the disease course in available case reports is usually mild and requires no additional antiviral treatment. We present the cases of COVID-19 relapse (COVID-19 rebound) in two patients following treatment with Paxlovid.

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