Nirmatrelvir je perorálně podávané antivirotikum zaměřené proti enzymu SARS-CoV-2 Mpro, který má zásadní význam v replikačním cyklu viru. Ritonavir působí jako inhibitor CYP3A4 a zvyšuje plazmatické hladiny nirmatrelviru. Kombinace nirmatrelviru a ritonaviru byla hodnocena v klinické studii EPIC-HR, ve které vedlo její užívání k signifikantnímu snížení rizika hospitalizace a úmrtí v důsledku COVID-19 v porovnání s placebem; účinnost této kombinace byla následně prokázána i u nemocných s variantou SARS-CoV-2 omikron. Kombinace nirmatrelviru a ritonaviru je indikována k léčbě onemocnění COVID-19 u dospělých pacientů, kteří nevyžadují doplňkovou léčbu kyslíkem a u nichž je zvýšené riziko progrese do závažné formy onemocnění COVID-19.

Nirmatrelvir is an orally administered antiviral agent targeted against SARS-CoV-2 Mpro enzyme, which is essential in replication cycle of the virus. Ritonavir acts as a CYP3A4 inhibitor and increases plasmatic levels of nirmatrelvir. The combination of nirmatrelvir and ritonavir was tested in the EPIC-HR clinical trial in which its administration led to a significant reduction in the risk of hospitalisation or death due to the COVID-19 disease compared to placebo; the efficacy of this combination was followingly demonstrated also in patients with the omicron variant of SARS-CoV-2. The combination of nirmatrelvir and ritonavir is indicated for the treatment of COVID-19 disease in adult patients, who do not require supplemental oxygen therapy and who are at increased risk of progression to a severe form of COVID-19.

• Klíčová slova
• nirmatrelvir,
• MeSH
• antivirové látky * aplikace a dávkování   farmakologie   MeSH
• COVID-19 mortalita   MeSH
• farmakoterapie COVID-19 * MeSH
• hospitalizace statistika a číselné údaje   MeSH
• klinická studie jako téma MeSH
• kombinovaná farmakoterapie MeSH
• lidé MeSH
• ritonavir aplikace a dávkování   farmakologie   MeSH
• riziko MeSH
• výsledek terapie MeSH
• Check Tag
• lidé MeSH

• Klíčová slova
• nirmatrelvir,
• MeSH
• antivirové látky * aplikace a dávkování   terapeutické užití   MeSH
• COVID-19 farmakoterapie   MeSH
• lidé MeSH
• vyvíjení léků MeSH
• Check Tag
• lidé MeSH

• Klíčová slova
• nirmatrelvir,
• MeSH
• antivirové látky * farmakologie   terapeutické užití   MeSH
• farmakoterapie COVID-19 * MeSH
• kombinovaná farmakoterapie MeSH
• lékové interakce * MeSH
• lidé MeSH
• ritonavir farmakologie   MeSH
• Check Tag
• lidé MeSH

• Klíčová slova
• nirmatrelvir/ritonavir,
• MeSH
• antivirové látky MeSH
• COVID-19 * MeSH
• hematologické nádory MeSH
• kohortové studie MeSH
• lidé MeSH
• výsledek terapie MeSH
• Check Tag
• lidé MeSH

• Klíčová slova
• molnupiravir, nirmatrelvir/ritonavir,
• MeSH
• antivirové látky MeSH
• COVID-19 * MeSH
• lidé MeSH
• výsledek terapie MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• metaanalýza MeSH

BACKGROUND: Nirmatrelvir/ritonavir treatment decreases the hospitalisation rate in immunocompetent patients with COVID-19, but data on efficacy in patients with haematological malignancy are scarce. Here, we describe the outcome of nirmatrelvir/ritonavir treatment in a large cohort of the latter patients. METHODS: This is a retrospective cohort study from the multicentre EPICOVIDEHA registry (NCT04733729) on patients with haematological malignancy, who were diagnosed with COVID-19 between January and September 2022. Patients receiving nirmatrelvir/ritonavir were compared to those who did not. A logistic regression was run to determine factors associated with nirmatrelvir/ritonavir administration in our sample. Mortality between treatment groups was assessed with Kaplan-Meier survival plots after matching all the patients with a propensity score. Additionally, a Cox regression was modelled to detect factors associated with mortality in patients receiving nirmatrelvir/ritonavir. FINDINGS: A total of 1859 patients were analysed, 117 (6%) were treated with nirmatrelvir/ritonavir, 1742 (94%) were treated otherwise. Of 117 patients receiving nirmatrelvir/ritonavir, 80% had received ≥1 anti-SARS-CoV-2 vaccine dose before COVID-19 onset, 13% of which received a 2nd vaccine booster. 5% were admitted to ICU. Nirmatrelvir/ritonavir treatment was associated with the presence of extrapulmonary symptoms at COVID-19 onset, for example anosmia, fever, rhinitis, or sinusitis (aOR 2.509, 95%CI 1.448-4.347) and 2nd vaccine booster (aOR 3.624, 95%CI 1.619-8.109). Chronic pulmonary disease (aOR 0.261, 95%CI 0.093-0.732) and obesity (aOR 0.105, 95%CI 0.014-0.776) were not associated with nirmatrelvir/ritonavir use. After propensity score matching, day-30 mortality rate in patients treated with nirmatrelvir/ritonavir was 2%, significantly lower than in patients with SARS-CoV-2 directed treatment other than nirmatrelvir/ritonavir (11%, p = 0.036). No factor was observed explaining the mortality difference in patients after nirmatrelvir/ritonavir administration. INTERPRETATION: Haematological malignancy patients were more likely to receive nirmatrelvir/ritonavir when reporting extrapulmonary symptoms or 2nd vaccine booster at COVID-19 onset, as opposed to chronic pulmonary disease and obesity. The mortality rate in patients treated with nirmatrelvir/ritonavir was lower than in patients with targeted drugs other than nirmatrelvir/ritonavir. FUNDING: EPICOVIDEHA has received funds from Optics COMMIT (COVID-19 Unmet Medical Needs and Associated Research Extension) COVID-19 RFP program by GILEAD Science, United States (Project 2020-8223).

• Publikační typ
• časopisecké články MeSH

• Klíčová slova
• nirmatrelvir,
• MeSH
• COVID-19 * terapie   MeSH
• dospělí MeSH
• inhibitory virových proteáz * aplikace a dávkování   MeSH
• lidé středního věku MeSH
• lidé MeSH
• ritonavir aplikace a dávkování   MeSH
• riziko MeSH
• senioři MeSH
• statistika jako téma MeSH
• výsledek terapie MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• klinické zkoušky MeSH
• multicentrická studie MeSH
• randomizované kontrolované studie MeSH

• Publikační typ
• zprávy MeSH

INTRODUCTION: Molnupiravir and nirmatrelvir/ritonavir are antivirals used to prevent progression to severe SARS-CoV-2 infections and decrease hospitalisation and mortality rates. Nirmatrelvir/ritonavir was authorised in Europe in December 2021, whereas molnupiravir is not yet licensed in Europe as of February 2022. Molnupiravir may be an alternative to nirmatrelvir/ritonavir because it is associated with fewer drug-drug interactions and contraindications. A caveat for molnupiravir is the mode of action induces viral mutations. Mortality rate reduction with molnupiravir was less pronounced than that with nirmatrelvir/ritonavir in patients without haematological malignancy. Little is known about the comparative efficacy of the two drugs in patients with haematological malignancy at high-risk of severe COVID-19. Thus, molnupiravir and nirmatrelvir/ritonavir were compared in a cohort of patients with haematological malignancies. METHODS: Clinical data from patients treated with molnupiravir or nirmatrelvir/ritonavir monotherapy for COVID-19 were retrieved from the EPICOVIDEHA registry. Patients treated with molnupiravir were matched by sex, age (±10 years), and severity of baseline haematological malignancy to controls treated with nirmatrelvir/ritonavir. RESULTS: A total of 116 patients receiving molnupiravir for the clinical management of COVID-19 were matched to an equal number of controls receiving nirmatrelvir/ritonavir. In each of the groups, 68 (59%) patients were male; with a median age of 64 years (interquartile range [IQR] 53-74) for molnupiravir recipients and 64 years (IQR 54-73) for nirmatrelvir/ritonavir recipients; 56.9% (n=66) of the patients had controlled baseline haematological malignancy, 12.9% (n=15) had stable disease, and 30.2% (n=35) had active disease at COVID-19 onset in each group. During COVID-19 infection, one third of patients from each group were admitted to hospital. Although a similar proportion of patients in the two groups were vaccinated (molnupiravir n=77, 66% vs. nirmatrelvir/ritonavir n=87, 75%), more of those treated with nirmatrelvir/ritonavir had received four vaccine doses (n=27, 23%) compared with those treated with molnupiravir (n=5, 4%) (P<0.001). No differences were detected in COVID-19 severity (P=0.39) or hospitalisation (P=1.0). No statistically significant differences were identified in overall mortality rate (P=0.78) or survival probability (d30 P=0.19, d60 P=0.67, d90 P=0.68, last day of follow up P=0.68). Deaths were either attributed to COVID-19, or the infection was judged by the treating physician to have contributed to death. CONCLUSIONS: Hospitalisation and mortality rates with molnupiravir were comparable to those with nirmatrelvir/ritonavir in high-risk patients with haematological malignancies and COVID-19. Molnupiravir is a plausible alternative to nirmatrelvir/ritonavir for COVID-19 treatment in patients with haematological malignancy.

• MeSH
• antivirové látky terapeutické užití   MeSH
• COVID-19 * MeSH
• farmakoterapie COVID-19 MeSH
• hematologické nádory * komplikace   farmakoterapie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• ritonavir terapeutické užití   MeSH
• SARS-CoV-2 MeSH
• senioři MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Geografické názvy
• Evropa MeSH

• Klíčová slova
• nirmatrelvir,
• MeSH
• antivirové látky * farmakologie   terapeutické užití   MeSH
• farmakoterapie COVID-19 * MeSH
• kardiovaskulární nemoci farmakoterapie   MeSH
• kombinovaná farmakoterapie MeSH
• lékové interakce MeSH
• lidé MeSH
• ritonavir farmakologie   MeSH
• Check Tag
• lidé MeSH