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Introduction: The comparative efficacy and safety of lorlatinib, a third-generation anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor (TKI), versus second-generation ALK TKIs as a first-line treatment for ALK+ advanced/metastatic nonsmall cell lung cancer (NSCLC) remains uncertain as there are no head-to-head clinical trials., Methods: Matching-adjusted indirect comparisons (MAICs) were conducted using phase III trial data demonstrating superior efficacy over crizotinib, a first-generation ALK TKI. MAICs were conducted to compare lorlatinib (CROWN) versus alectinib (ALEX and ALESIA) and brigatinib (ALTA-1L) with matching based on prespecified effect modifiers. Efficacy outcomes included progression-free survival (PFS), objective response (OR), and time to progression in the central nervous system (TTP-CNS). Safety outcomes included Grade ≥3 adverse events (AEs) and AEs leading to treatment discontinuation, dose reduction, or dose interruption., Results: Lorlatinib was estimated to improve PFS compared to alectinib (ALEX) (HR: 0.54 [95% CI: 0.33, 0.88]) and brigatinib (ALTA-1L) (HR: 0.51 [95% CI: 0.31, 0.82]). Lorlatinib was estimated to improve TTP-CNS compared with brigatinib (HR: 0.19 [95% CI: 0.05, 0.71]). The estimated Grade ≥3 AE rate was higher with lorlatinib than with alectinib (RR: 1.48 [95% CI: 1.13, 1.94]); however, no differences were observed in other safety endpoints (ie, AEs leading to discontinuation, dose reduction, or interruption) or compared to brigatinib., Conclusion: Lorlatinib was estimated to have superior efficacy over first- and second-generation ALK-TKIs, but a higher rate of Grade ≥3 AEs compared to alectinib. These data support the use of lorlatinib as a first-line treatment for ALK+ advanced/metastatic NSCLC., Competing Interests: Disclosure Devin Abrahami, Anna Polli, Haitao Chu, and Despina Thomaidou are employees of Pfizer and have stock ownership in Pfizer. John Mark Kelton was employed by Pfizer during the conduct of this study, and has stock ownership in Pfizer, Abbott and AbbVie. Christine Garcia receives consulting fees from Pfizer. Todd Bauer receives consulting fees from and is an ad board member of Pfizer, Bayer, and Lilly. Conor Chandler and Min Tan are employees of Evidera, which received financial support from Pfizer in connection with the study and the development of this manuscript., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Objectives: Lorlatinib, a brain-penetrant, third-generation anaplastic lymphoma kinase (ALK) inhibitor, demonstrated robust overall and intracranial antitumor activity in patients with advanced ALK-positive non-small cell lung cancer (NSCLC) previously treated with an ALK inhibitor in a global phase 1/2 study (NCT01970865) and a multicenter phase 2 study conducted in China (NCT03909971). We report updated 3-year follow-up data from the phase 2 study., Materials and Methods: Chinese patients with locally advanced or metastatic ALK-positive NSCLC that progressed after crizotinib as the only prior ALK inhibitor (cohort 1) or after 1 non-crizotinib ALK inhibitor (cohort 2), were enrolled in the study. All patients received lorlatinib 100 mg once daily., Results: At data cutoff, of 109 enrolled patients, the median duration of follow-up for progression-free survival (PFS) was 35.8 months in cohort 1 (n = 67) and 33.1 months in cohort 2 (n = 42). Median PFS (95% CI) per independent central review was 26.3 months (16.6-35.9) and 5.6 months (2.9-12.4), respectively. The median duration of follow-up for overall survival (OS) was 36.4 months and 37.5 months, respectively. Median OS (95% CI) was not reached (NR; NR-NR) and 21.9 months (11.9-NR), respectively. Median intracranial time to progression (95% CI) was NR (NR-NR) and NR (9.7 months-NR), respectively. No new safety signals emerged with long-term treatment., Conclusion: The long-term data confirm robust overall and intracranial clinical activity of lorlatinib, with no new safety signals emerging. These results support using lorlatinib in Chinese patients with previously treated ALK-positive NSCLC with or without brain metastases., Clinicaltrials: gov NCT03909971., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose: Lorlatinib improved progression-free survival (PFS) and intracranial activity versus crizotinib in patients with previously untreated, advanced, ALK -positive non-small cell lung cancer (NSCLC) in the phase III CROWN study. Here, we report long-term outcomes from CROWN after 5 years of follow-up., Methods: Two hundred ninety-six patients with ALK -positive NSCLC were randomly assigned 1:1 to receive lorlatinib 100 mg once daily (n = 149) or crizotinib 250 mg twice daily (n = 147). This post hoc analysis presents updated investigator-assessed efficacy outcomes, safety, and biomarker analyses., Results: With a median follow-up for PFS of 60.2 and 55.1 months, respectively, median PFS was not reached (NR [95% CI, 64.3 to NR]) with lorlatinib and 9.1 months (95% CI, 7.4 to 10.9) with crizotinib (hazard ratio [HR], 0.19 [95% CI, 0.13 to 0.27]); 5-year PFS was 60% (95% CI, 51 to 68) and 8% (95% CI, 3 to 14), respectively. Median time to intracranial progression was NR (95% CI, NR to NR) with lorlatinib and 16.4 months (95% CI, 12.7 to 21.9) with crizotinib (HR, 0.06 [95% CI, 0.03 to 0.12]). Safety profile was consistent with that in prior analyses. Emerging new ALK resistance mutations were not detected in circulating tumor DNA collected at the end of lorlatinib treatment., Conclusion: After 5 years of follow-up, median PFS has yet to be reached in the lorlatinib group, corresponding to the longest PFS ever reported with any single-agent molecular targeted treatment in advanced NSCLC and across all metastatic solid tumors. These results coupled with prolonged intracranial efficacy and absence of new safety signals represent an unprecedented outcome for patients with advanced ALK -positive NSCLC and set a new benchmark for targeted therapies in cancer.

Patients with anaplastic lymphoma kinase (ALK)-driven neuroblastoma may respond to tyrosine kinase inhibitors, but resistance to treatment occurs and methods currently used for detection of residual disease have limited sensitivity. Here, we present a national unselected cohort of five patients with relapsed or refractory ALK-driven neuroblastoma treated with lorlatinib as monotherapy and test the potential of targeted circulating tumor DNA (ctDNA) analysis as a guide for treatment decisions in these patients. We developed a sequencing panel for ultrasensitive detection of ALK mutations associated with neuroblastoma or resistance to tyrosine kinase inhibitors and used it for ctDNA analysis in 83 plasma samples collected longitudinally from the four patients who harbored somatic ALK mutations. All four patients with ALK p.R1275Q experienced major responses and were alive 35 to 61 months after starting lorlatinib. A fifth patient with ALK p.F1174L initially had a partial response but relapsed after 10 months of treatment. In all cases, ctDNA was detected at the start of lorlatinib single-agent treatment and declined gradually, correlating with clinical responses. In the two patients exhibiting relapse, ctDNA increased 9 and 3 months, respectively, before clinical detection of disease progression. In one patient harboring HRAS p.Q61L in the relapsed tumor, retrospective ctDNA analysis showed that the mutation appeared de novo after 8 months of lorlatinib treatment. We conclude that some patients with relapsed or refractory high-risk neuroblastoma show durable responses to lorlatinib as monotherapy, and targeted ctDNA analysis is effective for evaluation of treatment and early detection of relapse in ALK-driven neuroblastoma., Significance: We present five patients with ALK-driven relapsed or refractory neuroblastoma treated with lorlatinib as monotherapy. All patients responded to treatment, and four of them were alive after 3 to 5 years of follow-up. We performed longitudinal ctDNA analysis with ultra-deep sequencing of the ALK tyrosine kinase domain. We conclude that ctDNA analysis may guide treatment decisions in ALK-driven neuroblastoma, also when the disease is undetectable using standard clinical methods., (©2024 The Authors; Published by the American Association for Cancer Research.)

Feline infectious peritonitis (FIP) is a fatal illness caused by a mutated feline coronavirus (FCoV). This disease is characterized by its complexity, resulting from systemic infection, antibody-dependent enhancement (ADE), and challenges in accessing effective therapeutics. Extract derived from Vigna radiata (L.) R. Wilczek (VRE) exhibits various pharmacological effects, including antiviral activity. This study aimed to investigate the antiviral potential of VRE against FCoV, addressing the urgent need to advance the treatment of FIP. We explored the anti-FCoV activity, antiviral mechanism, and combinational application of VRE by means of in vitro antiviral assays. Our findings reveal that VRE effectively inhibited the cytopathic effect induced by FCoV, reduced viral proliferation, and downregulated spike protein expression. Moreover, VRE blocked FCoV in the early and late infection stages and was effective under in vitro ADE infection. Notably, when combined with VRE, the polymerase inhibitor GS-441524 or protease inhibitor GC376 suppressed FCoV more effectively than monotherapy. In conclusion, this study characterizes the antiviral property of VRE against FCoV in vitro , and VRE possesses therapeutic potential for FCoV treatment.

Background: The effectiveness of nirmatrelvir-ritonavir has mainly been shown in non-hospitalized patients with mild-to-moderate coronavirus disease 2019 (COVID-19). The real-world effectiveness of nirmatrelvir-ritonavir urgently needs to be determined using representative in-hospital patients with COVID-19 during the Omicron wave of the pandemic., Methods: We performed a multicentre, retrospective study in five Chinese PLA General Hospital medical centers in Beijing, China. Patients hospitalized with COVID-19 from 10 December 2022 to 20 February 2023 were eligible for inclusion. A 1:1 propensity score matching was performed between the nirmatrelvir-ritonavir group and the control group., Results: 1010 recipients of nirmatrelvir-ritonavir and 1010 matched controls were finally analyzed after matching. Compared with matched controls, the nirmatrelvir-ritonavir group had a lower incidence rate of all-cause death (4.6/1000 vs. 6.3/1000 person-days, p  = 0.013) and a higher incidence rate of clinical improvement (47.6/1000 vs. 45.8/1000 person-days, p  = 0.012). Nirmatrelvir-ritonavir was associated with a 22% lower all-cause mortality and a 14% higher incidence of clinical improvement. Initiation of nirmatrelvir-ritonavir within 5 days after symptom onset was associated with a 50% lower mortality and a 26% higher clinical improvement rate. By contrast, no significant associations were identified among patients receiving nirmatrelvir-ritonavir treatment more than 5 days after symptom onset. Nirmatrelvir-ritonavir was also associated with a 50% increase in survival days and a 12% decrease in days to clinical improvement., Conclusion: Among hospitalized patients with COVID-19 during the Omicron wave in Beijing, China, the early initiation of nirmatrelvir-ritonavir was associated with clinical benefits of lowering mortality and improving clinical recovery.

A simple, Accurate, precise method was developed for the estimation of the Lorlatinib in API form and Marketed pharmaceutical dosage form by RP-HPLC. Chromatogram was run through Hypersil C18 (4.6mm×150mm, 5µm) Particle size Column and Mobile phase containing Methanol and Water taken in the ratio of 25: 75% v/v was pumped through column at a flow rate of 1.0 ml/min. Temperature was maintained at 38ºC. Optimized wavelength selected was 310 nm. Retention times of Lorlatinib were found to be 3.513 minutes respectively. The %RSD for the Repeatability and Intermediate Precision of the Lorlatinib were found to be within limits. %Recovery was obtained 98.96% and it was found to be within the limits for Lorlatinib respectively. The LOD, LOQ values obtained from regression equations of Lorlatinib were 0.332µg/ml and 1.0078 µg/ml respectively. Regression equation of Lorlatinib was found to be y = 39948x + 16821 respectively. The Retention times was decreased and run time was decreased, so the method developed was simple and economical that can be adopted in regular Quality control test in Industries.

The use of anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs), such as lorlatinib, for the treatment of patients with ALK gene rearrangement (or ALK-positive) non-small cell lung cancer (NSCLC) has been shown to improve the overall survival and quality of life of these patients. However, lorlatinib is not exempt from potential adverse events. Adequate monitoring and management of these adverse events are critical for increasing patient adherence to lorlatinib, thereby maximizing the benefits of treatment and minimizing the risks associated with treatment discontinuation. Considering that the adverse events of lorlatinib can affect different organs and systems, the participation of a multidisciplinary team, including cardiologists, neurologists, internal medicine specialists, and oncology pharmacists, is needed. This article presents specific and pragmatic strategies for identifying and treating the most relevant adverse events associated with lorlatinib in patients with advanced ALK-positive NSCLC based on the clinical experience of a multidisciplinary panel of experts., (© 2024. The Author(s).)

Background: Anaplastic lymphoma kinase (ALK) rearrangements are rare in non-myofibroblastic sarcoma and there is limited data on the efficacy of ALK tyrosine kinase inhibitors (TKIs) and mechanisms of resistance in these patients., Case: A 58 year-old man with metastatic non-myofibroblastic sarcoma was found to have an EML4-ALK fusion on molecular sequencing. After progression on first line systemic therapy with doxorubicin, the patient received alectinib, a second generation ALK inhibitor, and had a marked clinical and radiological response. He progressed after 5 months of treatment. Repeat lung biopsy identified the emergence of an ALK I1171N resistance mutation. He was then treated with lorlatinib, again with rapid clinical improvement and significant partial radiological response. He progressed after 4 months, at which time a repeat lung biopsy identified a new ALK kinase domain mutation G1202R. The patient was subsequently treated with chemotherapy, though unfortunately died shortly after due to rapidly progressive disease., Conclusion: This case report adds to a body of evidence demonstrating the potential transformative response to targeted therapy in non-lung solid organ tumours harbouring ALK fusions. This is the first description tracking the development of resistance mutations in a patient with non-myofibroblastic sarcoma and questions the utility of the presence of G1202R mutation as a marker of lorlatinib sensitivity in non-lung ALK rearranged tumours, contrary to experience in lung cancer., (© 2024 The Author(s). Cancer Reports published by Wiley Periodicals LLC.)

Objectives: To analyse the impact of the most clinically relevant β-lactamases and their interplay with low outer membrane permeability on the activity of cefiderocol, ceftazidime/avibactam, aztreonam/avibactam, cefepime/enmetazobactam, cefepime/taniborbactam, cefepime/zidebactam, imipenem/relebactam, meropenem/vaborbactam, meropenem/xeruborbactam and meropenem/nacubactam against recombinant Escherichia coli strains., Methods: We constructed 82 E. coli laboratory transformants expressing the main β-lactamases circulating in Enterobacterales (70 expressing single β-lactamase and 12 producing double carbapenemase) under high (E. coli TG1) and low (E. coli HB4) permeability conditions. Antimicrobial susceptibility testing was determined by reference broth microdilution., Results: Aztreonam/avibactam, cefepime/zidebactam, cefiderocol, meropenem/xeruborbactam and meropenem/nacubactam were active against all E. coli TG1 transformants. Imipenem/relebactam, meropenem/vaborbactam, cefepime/taniborbactam and cefepime/enmetazobactam were also highly active, but unstable against most of MBL-producing transformants. Combination of β-lactamases with porin deficiency (E. coli HB4) did not significantly affect the activity of aztreonam/avibactam, cefepime/zidebactam, cefiderocol or meropenem/nacubactam, but limited the effectiveness of the rest of carbapenem- and cefepime-based combinations. Double-carbapenemase production resulted in the loss of activity of most of the compounds tested, an effect particularly evident for those E. coli HB4 transformants in which MBLs were present., Conclusions: Our findings highlight the promising activity that cefiderocol and new β-lactam/β-lactamase inhibitors have against recombinant E. coli strains expressing widespread β-lactamases, including when these are combined with low permeability or other enzymes. Aztreonam/avibactam, cefiderocol, cefepime/zidebactam and meropenem/nacubactam will help to mitigate to some extent the urgency of new compounds able to resist MBL action, although NDM enzymes represent a growing challenge against which drug development efforts are still needed., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

During our screening for anti-mycobacterial agents against Mycobacterium avium complex (MAC), two new polycyclic tetramate macrolactams (PTMs), named hydroxycapsimycin (1) and brokamycin (2), were isolated along with the known PTM, ikarugamycin (3), from the culture broth of marine-derived Streptomyces sp. KKMA-0239. The relative structures of 1 and 2 were elucidated by spectroscopic data analyses, including 1D and 2D NMR. Furthermore, the absolute configuration of 1 was confirmed by a single-crystal X-ray diffraction analysis. Compounds 2 and 3 exhibited moderate antimycobacterial activities against MAC, including clinically isolated drug-resistant M. avium., (© 2024. The Author(s), under exclusive licence to the Japan Antibiotics Research Association.)

As the SARS-CoV-2 virus continues to spread and mutate, it remains important to focus not only on preventing spread through vaccination but also on treating infection with direct-acting antivirals (DAA). The approval of Paxlovid, a SARS-CoV-2 main protease (M pro ) DAA, has been significant for treatment of patients. A limitation of this DAA, however, is that the antiviral component, nirmatrelvir, is rapidly metabolized and requires inclusion of a CYP450 3A4 metabolic inhibitor, ritonavir, to boost levels of the active drug. Serious drug-drug interactions can occur with Paxlovid for patients who are also taking other medications metabolized by CYP4503A4, particularly transplant or otherwise immunocompromised patients who are most at risk for SARS-CoV-2 infection and the development of severe symptoms. Developing an alternative antiviral with improved pharmacological properties is critical for treatment of these patients. By using a computational and structure-guided approach, we were able to optimize a 100 to 250 μM screening hit to a potent nanomolar inhibitor and lead compound, Mpro61. In this study, we further evaluate Mpro61 as a lead compound, starting with examination of its mode of binding to SARS-CoV-2 M pro . In vitro pharmacological profiling established a lack of off-target effects, particularly CYP450 3A4 inhibition, as well as potential for synergy with the currently approved alternate antiviral, molnupiravir. Development and subsequent testing of a capsule formulation for oral dosing of Mpro61 in B6-K18-hACE2 mice demonstrated favorable pharmacological properties, efficacy, and synergy with molnupiravir, and complete recovery from subsequent challenge by SARS-CoV-2, establishing Mpro61 as a promising potential preclinical candidate., Competing Interests: Competing interests statement:Yale University has filed a patent application covering Mpro61.

The CLIP1-LTK fusion was recently discovered as a novel oncogenic driver in non-small cell lung cancer (NSCLC). Lorlatinib, a third-generation ALK inhibitor, exhibited a dramatic clinical response in a NSCLC patient harboring CLIP1-LTK fusion. However, it is expected that acquired resistance will inevitably develop, particularly by LTK mutations, as observed in NSCLC induced by oncogenic tyrosine kinases treated with corresponding tyrosine kinase inhibitors (TKIs). In this study, we evaluate eight LTK mutations corresponding to ALK mutations that lead to on-target resistance to lorlatinib. All LTK mutations show resistance to lorlatinib with the L650F mutation being the highest. In vitro and in vivo analyses demonstrate that gilteritinib can overcome the L650F-mediated resistance to lorlatinib. In silico analysis suggests that introduction of the L650F mutation may attenuate lorlatinib-LTK binding. Our study provides preclinical evaluations of potential on-target resistance mutations to lorlatinib, and a novel strategy to overcome the resistance., (© 2024. The Author(s).)

Background: ROS1 fusion-positive (ROS1+) nonsmall cell lung cancer (NSCLC) patients are highly sensitive to tyrosine kinase inhibitor (TKI) treatments. However, acquired TKI resistance remains the major hurdle preventing patients from experiencing prolonged benefits., Methods: 107 advanced or metastatic ROS1+ NSCLC patients who progressed on crizotinib and lorlatinib were recruited. Tissue and plasma samples were collected at baseline (N = 50), postcrizotinib (N = 91), and postlorlatinib (N = 21), which were all subject to the 139-gene targeted next-generation DNA sequencing. Molecular dynamics modeling was performed to investigate the effects of ROS1 mutations on binding to different TKIs., Results: In patients with postcrizotinib and postlorlatinib samples, an accumulation of on- and off-target resistance alterations after multiple TKI treatments was observed. ROS1 G2032R and MET amplification were the most common on-target and off-target alterations, respectively. Patients with CD74-ROS1 and SLC34A2-ROS1 had longer progression-free survival (PFS) (P < 0.001) and higher rates of resistance mutations (on-target, P = 0.001; off-target, P = 0.077) than other ROS1 fusion variants following crizotinib treatment. Ten distinct on-target resistance mutations were detected after TKI therapies, of which 4 were previously unreported (ROS1 L2010M, G1957A, D1988N, L1982V). Molecular dynamics simulations showed that all 4 mutations were refractory to crizotinib, while G1957A, D1988N, and L1982V were potentially sensitive to lorlatinib and entrectinib., Conclusions: This study provided a comprehensive portrait of TKI-resistance mechanisms in ROS1+ NSCLC patients. Using in silico simulations of TKI activity, novel secondary mutations that may confer TKI resistance were identified and may support clinical therapeutic decision-making., (© Association for Diagnostics & Laboratory Medicine 2024. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: In the USA, nirmatrelvir/ritonavir is authorized for the treatment of mild-to-moderate COVID-19 in patients at least 12 years of age, at high risk for progression to severe COVID-19., Objectives: To estimate the impact of outpatient nirmatrelvir/ritonavir on COVID-19 hospitalization risk in a US healthcare system., Methods: We conducted a cohort study using electronic health records among outpatients with a positive SARS-CoV-2 PCR test between January and August 2022. We evaluated the association of nirmatrelvir/ritonavir therapy with time to hospitalization by estimating adjusted HRs and assessed the impact of nirmatrelvir/ritonavir on predicted COVID-19 hospitalizations using machine-learning methods., Results: Among 44 671 patients, 4948 (11%) received nirmatrelvir/ritonavir, and 201 (0.4%) were hospitalized within 28 days of COVID-19 diagnosis. Nirmatrelvir/ritonavir recipients were more likely to be older, white, vaccinated, have comorbidities and reside in areas with higher average socioeconomic status. The 28 day cumulative incidence of hospitalization was 0.06% (95% CI: 0.02%-0.17%) among nirmatrelvir/ritonavir recipients and 0.52% (95% CI: 0.46%-0.60%) among non-recipients. For nirmatrelvir/ritonavir versus no therapy, the age-adjusted HR was 0.08 (95% CI: 0.03-0.26); the fully adjusted HR was 0.16 (95% CI: 0.05-0.50). In the machine-learning model, the primary features reducing predicted hospitalization risk were nirmatrelvir/ritonavir, younger age, vaccination, female gender and residence in a higher socioeconomic status area., Conclusions: COVID-19 hospitalization risk was reduced by 84% among nirmatrelvir/ritonavir recipients in a large, diverse healthcare system during the Omicron wave. These results suggest that nirmatrelvir/ritonavir remained highly effective in a setting substantially different than the original clinical trials., (© The Author(s) 2024. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Two new pramanicin analogs, named virgaricins C (1) and D (2), were discovered by physicochemical screening from a static cultured material of Apiospora sp. FKI-8058. Their structures were elucidated by MS and NMR analyses and chemical derivatization. Compounds 1 and 2 showed moderate antimalarial activity and cytotoxicity., (© 2024. The Author(s), under exclusive licence to the Japan Antibiotics Research Association.)

In this original research we present new emerging data in COVID-19 that create urgent challenges for health providers in prevention and treatment. Health providers should be aware that COVID-19 cases, hospitalizations, and deaths have increased markedly in August 2023. Further, recent data demonstrate a new emerging strain resistant to prior natural and vaccine immunity. The most recent emerging data show that only this updated COVID-19 vaccine produces the same immune response as previous vaccines that reduced mortality by over 95 % and morbidity by over 99 %. This recommendation encompasses all adults and children aged 6 months and older, regardless of whether they have had a prior COVID-19 infection or even if they have never received a prior vaccination. This updated COVID-19 vaccine, approved in September 2023, will be the best means to prevent COVID-19 during this upcoming season of respiratory viruses. In the meanwhile, all members of the US population regardless of previous natural infection, vaccines, or boosters are equally susceptible. At present, health providers should counsel all their patients about masking, social distancing, and avoiding crowds, especially indoors where regions of extreme weather conditions are keeping people indoors in closed quarters. In the treatment of COVID-19 the major clinical challenge to health providers, especially in their Black patients, is to prescribe Paxlovid during the first 5 days after onset of symptoms and a positive test., (Copyright © 2024 National Medical Association. Published by Elsevier Inc. All rights reserved.)

Introduction: The objective of this report is to describe the clinical pathway for early treatment of patients with acute SARS-CoV-2 infection and to evaluate the first results of its implementation., Methods: This is a descriptive and retrospective study of the implementation of a clinical pathway of treatment in outpatients (January 1 to June 30 2022). Clinical pathway: detection and referral systems from Primary Care, Emergency services, hospital specialities and an automated detection system; clinical evaluation and treatment administration in the COVID-19 day-hospital and subsequent clinical follow-up. Explanatory variables: demographics, comorbidity, vaccination status, referral pathways and treatment administration., Outcome Variables: hospitalization and death with 30 days, grade 2-3 toxicity related to treatment., Results: Treatment was administered to 262 patients (53,4% women, median age 60 years). The treatment indication criteria were immunosupression (68,3%), and the combination of age, vaccination status and comorbidity in the rest 47,3% of the patients s received remdesivir, 35,9% nirmatrelvir/ritonavir, 13,4% sotrovimab and 2,4% combined treatment with a median of 4 days after symptom onset. Hospital admission was required for 6,1% of the patients, 3,8% related to progression COVID-19. No patient died. Toxicity grade 2-3 toxicity was reported in 18,7%, 89,8% dysgeusia and metallic tasted related nirmatrelvir/ritonavir. Seven patients discontinued treatment due to toxicity., Conclusion: The creation and implementation of a clinical pathway for non-hospitalized patients with SARS-CoV-2 infection is effective and it allows early accessibility and equity of currently available treatments., (Copyright © 2022 Sociedad Española de Enfermedades Infecciosas y Microbiología Clínica. Published by Elsevier España, S.L.U. All rights reserved.)

Vicenistatin (1) is a 20-membered polyketide macrocyclic antibiotic with potent antimicrobial and cytotoxic activities. In this study, to further explore the potential of 1 as candidates of antibacterial drug development, 4'-N-demethyl vicenistatin (2), a secondary metabolite obtained from the ∆vicG mutant strain of Monodonata labio-associated Streptomyces parvus SCSIO Mla-L010, was utilized as a starting material for modifications of 4'-amino group of vicenistatin. Six new vicenistatin derivatives (3-8) were semi-synthesized through a concise route of amino modification with various aliphatic and aromatic aldehydes. Our study reveals that the bioactivity of vicenistatin is closely related to amino modification in sugar moiety, which results from the length of alkyl side chain as well as the presence of electron withdrawing/denoting group on the benzene ring. Importantly, compounds 4 with a butyl group and 8 with a 3,5-dihydroxyl-benzyl group at 4'-amino group, respectively, exhibited good antimicrobial activities, with MIC values spanning 0.5-4 μg ml -1 to Gram-positive pathogens, including methicillin-resistant Staphylococcus aureus, methicillin-resistant Staphylococcus epidermidis, Micrococcus luteus and Bacillus subtilis, with low cytotoxicity. This research promotes the further exploration of structure-activity relationships of vicenistatin and provides new vicenistatin derivatives for development of future anti-infectious agents with reduced cytotoxicity., (© 2024. The Author(s), under exclusive licence to the Japan Antibiotics Research Association.)

A clear understanding of real-world uptake of nirmatrelvir-ritonavir for treatment of SARS-CoV-2 can inform treatment allocation strategies and improve interpretation of effectiveness studies. We used data from a large US healthcare system to describe nirmatrelvir-ritonavir dispenses among all SARS-CoV-2 positive patients aged ≥ 12 years meeting recommended National Institutes of Health treatment eligibility criteria for the study period between 1 January and 31 December, 2022. Overall, 10.9% (N = 34,791/319,900) of treatment eligible patients with SARS-CoV-2 infections received nirmatrelvir-ritonavir over the study period. Although uptake of nirmatrelvir-ritonavir increased over time, by the end of 2022, less than a quarter of treatment eligible patients with SARS-CoV-2 infections had received nirmatrelvir-ritonavir. Across patient demographics, treatment was generally consistent with tiered treatment guidelines, with dispenses concentrated among patients aged ≥ 65 years (14,706/63,921; 23.0%), and with multiple comorbidities (10,989/54,431; 20.1%). However, neighborhoods of lower socioeconomic status (upper third of neighborhood deprivation index [NDI]) had between 12% (95% CI: 7-18%) and 28% (25-32%) lower odds of treatment dispense over the time periods studied compared to the lower third of NDI distribution, even after accounting for demographic and clinical characteristics. A limited chart review (N = 40) confirmed that in some cases a decision not to treat was appropriate and aligned with national guidelines to use clinical judgement on a case-by-case basis. There is a need to enhance patient and provider awareness on the availability and benefits of nirmatrelvir-ritonavir for the treatment of COVID-19 illness., (© 2024. The Author(s).)

Nirmatrelvir/ritonavir is a promising option for preventing severe COVID-19 in solid organ transplant recipients with SARS-CoV-2 infection. However, concerns have arisen regarding potential drug interactions with calcineurin inhibitors (CNI). This two-phase multicentre retrospective study, involving 113 patients on tacrolimus and 13 on cyclosporine A, aimed to assess the feasibility and outcomes of recommendations issued by The French societies of transplantation (SFT) and pharmacology (SFPT) for CNI management in this context. The study first evaluated adherence to recommendations, CNI exposure, and clinical outcomes. Notably, 96.5% of patients on tacrolimus adhered to the recommendations, maintaining stable tacrolimus trough concentrations (C 0 ) during nirmatrelvir/ritonavir treatment. After reintroduction, most patients experienced increased C 0 , with 42.9% surpassing 15 ng/mL, including three patients exceeding 40 ng/mL. Similar trends were observed in cyclosporine A patients, with no COVID-19-related hospitalizations. Moreover, data from 22 patients were used to refine the reintroduction strategy. Modelling analyses suggested reintroducing tacrolimus at 50% of the initial dose on day 8, and then at 100% from day 9 as the optimal approach. In conclusion, the current strategy effectively maintains consistent tacrolimus exposure during nirmatrelvir/ritonavir treatment, and a stepwise reintroduction of tacrolimus may be better suited to the low CYP3A recovery., Competing Interests: AD reports consultancy fees from Alnylam and Merck outside the submitted work. CM reports research grants (paid to institution), financial support for participation in congresses, and expertise fees from Chiesi and Astellas. StB received lecture fees from Astellas. BG reports financial support for participation in congresses from Chiesi and Gilead, speaker for Gilead, outside the submitted work. LC received lecture fees from Astellas, Chiesi, Novartis, Sandoz, Ostuka, GSK, and Biotest, and participated in advisory boards for Biotest, Hansa, and Novartis. LE received fees from Astellas, Chiesi, and Sandoz. FL received research grants (paid to institution) from Astellas, Sandoz, and Chiesi and fees to attend meetings from Viiv, MSD, Janssen-Cilag, Pfizer, and Gilead. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Boland, Devresse, Monchaud, Briol, Belaiche, Giguet, Couzi, Thaunat, Esposito, Meszaros, Roussoulieres, Haufroid, Le Meur and Lemaitre.)

Purpose: Besides the well-established efficacy in preventing severe COVID-19, the impact of early treatments, namely antivirals and monoclonal antibodies (mAbs), on the time length to negativization of SARS-CoV-2 nasal swabs is still unclear. The aim of this study was to compare the efficacy of different early treatments in reducing the SARS-CoV-2 viral shedding, identifying a single drug that might potentially lead to a more rapid negativization of SARS-CoV-2 nasal swab., Methods: This was a single-centre, retrospective, observational study conducted at Ospedale Luigi Sacco in Milan. Data of high-risk COVID-19 patients who received early treatments between 23 December 2021 and March 2023 were extracted. The comparison across treatments was conducted using the Kruskall-Wallis test for continuous variables. Dunn's test with Bonferroni adjustment was performed for post-hoc comparisons of days to negativization. Secondly, a negative binomial regression adjusted for age, sex, number of comorbidities, immunosuppression, and SARS-CoV-2 vaccination status was implemented., Results: Data from 428 patients receiving early treatments were collected. The majority were treated with Nirmatrelvir/Ritonavir and were affected by SARS-CoV-2 Omicron infection with BA.2 sublineage. The median length time to SARS-CoV-2 nasal swab negativization was 9 days [IQR 7-13 days]. We found that Nirmatrelvir/Ritonavir determined a significant decrease of the length time to SARS-CoV-2 nasal swab negativization compared to mAbs (p = 0.003), but not compared to Remdesivir (p = 0.147) and Molnupiravir (p = 0.156)., Conclusion: Our findings highlight the importance of promptly treating high-risk COVID-19 patients with Nirmatrelvir/Ritonavir, as it also contributes to achieving a faster time to negative SARS-CoV-2 nasal swabs., (© 2024. The Author(s).)

Objectives: Although guidelines recommend antiviral therapy for outpatients with COVID-19 who are at high risk of progressing to severe conditions, such as older adults, many patients do not receive appropriate treatment. Little is known, however, about the physician factors associated with the prescription of guideline-recommended antiviral therapy for patients with COVID-19., Design: A cross-sectional study., Setting: Data including outpatient visits in primary care clinics in Japan from April to August 2023., Participants: We analysed 30 953 outpatients aged ≥65 years treated with COVID-19 (mean (SD) age, 75.0 (7.6) years; 17 652 women (57.0%)) in 1394 primary care clinics., Outcome Measures: The primary outcome was the prescription of guideline-recommended antivirals (ie, nirmatrelvir-ritonavir or molnupiravir), adjusted for patient characteristics, months of visits and regions., Results: Antiviral prescriptions were concentrated among a small proportion of physicians; for example, the top 10% of physicians that had the largest number of nirmatrelvir-ritonavir prescriptions accounted for 92.4% of all nirmatrelvir-ritonavir prescriptions. After adjusting for potential confounders, physicians with higher patient volumes were more likely to prescribe guideline-recommended antivirals to their patients (adjusted OR (aOR) for high vs low volume, 1.76; 95% CI 1.31 to 2.38; adjusted p<0.001). We found no evidence that the likelihood of guideline-recommended antiviral prescription differed based on physicians' gender (aOR for women vs men, 1.24; 95% CI 0.88 to 1.74; adjusted p=0.48) or age (aOR for 45-59 vs <45 years, 1.16; 95% CI 0.87 to 1.54; adjusted p=0.48; aOR for ≥60 vs <45 years, 0.88; 95% CI 0.66 to 1.16; adjusted p=0.48). These patterns were similar when examining nirmatrelvir-ritonavir and molnupiravir separately., Conclusions: Our findings suggest that provider-level factors, such as the clinical experience of treating the patients with COVID-19, play an important role in the appropriate prescription of antiviral medications for COVID-19 in the primary care setting., Competing Interests: Competing interests: AM reported receiving consulting fees from M3, Inc., which provides the JAMDAS database used in this article, during the conduct of the study. KK, AI and DS reported receiving personal fees from M3, Inc. as employees during the conduct of the study; and personal fees from M3, Inc. as employees outside the submitted work. YT reported receiving grants from the National Institutes of Health (NIH)/National Institute on Aging (R01AG068633 & R01AG082991), NIH/National Institute on Minority Health and Health Disparities (R01MD013913) and Gregory Annenberg Weingarten GRoW @Annenberg outside the submitted work; and serving on the board of directors for M3, Inc., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Paxlovid has been shown to be effective in reducing mortality and hospitalization rates in patients with coronavirus disease 2019 (COVID-19). It is not known whether Paxlovid can reduce the risk of cardiovascular diseases (CVD) in COVID-19-surviving patients with autoimmune rheumatic diseases (AIRDs)., Methods: TriNetX data from the US Collaborative Network were used in this study. A total of 5,671,395 patients with AIRDs were enrolled between January 1, 2010, and December 31, 2021. People diagnosed with COVID-19 were included in the cohort (n = 238,142) from January 1, 2022, to December 31, 2022. The Study population was divided into two groups based on Paxlovid use. Propensity score matching was used to generate groups with matched baseline characteristics. The hazard ratios (HRs) and 95% confidence intervals of cardiovascular outcomes, admission rate, mortality rate, and intensive care unit (ICU) admission rate were calculated between Paxlovid and non-Paxlovid groups. Subgroup analyses on sex, age, race, autoimmune diseases group, and sensitivity analyses for Paxlovid use within the first day or within 2-5 days of COVID-19 diagnosis were performed., Results: Paxlovid use was associated with lower risks of cerebrovascular complications (HR = 0.65 [0.47-0.88]), arrhythmia outcomes (HR = 0.81 [0.68-0.94]), ischemic heart disease, other cardiac disorders (HR = 0.51 [0.35-0.74]) naming heart failure (HR = 0.41 [0.26-0.63]) and deep vein thrombosis (HR = 0.46 [0.24-0.87]) belonging to thrombotic disorders in AIRD patients with COVID-19. Compared with the Non-Paxlovid group, risks of major adverse cardiac events (HR = 0.56 [0.44-0.70]) and any cardiovascular outcome mentioned above (HR = 0.76 [0.66-0.86]) were lower in the Paxlovid group. Moreover, the mortality (HR = 0.21 [0.11-0.40]), admission (HR = 0.68 [0.60-0.76]), and ICU admission rates (HR = 0.52 [0.33-0.80]) were significantly lower in the Paxlovid group than in the non-Paxlovid group. Paxlovid appears to be more effective in male, older, and Black patients with AIRD. The risks of cardiovascular outcomes and severe conditions were reduced significantly with Paxlovid prescribed within the first day of COVID-19 diagnosis., Conclusions: Paxlovid use is associated with a lower risk of CVDs and severe conditions in COVID-19-surviving patients with AIRD., (© 2024. The Author(s).)

Introduction: The study of resistance-causing mutations in oncogene-driven tumors is fundamental to guide clinical decisions. Several point mutations affecting the ROS1 kinase domain have been identified in the clinical setting, but their impact requires further exploration, particularly in improved pre-clinical models. Given the scarcity of solid pre-clinical models to approach rare cancer subtypes like ROS1 + NSCLC, CRISPR/Cas9 technology allows the introduction of mutations in patient-derived cell lines for which resistant variants are difficult to obtain due to the low prevalence of cases within the clinical setting., Methods: In the SLC34A2-ROS1 rearranged NSCLC cell line HCC78, we knocked-in through CRISPR/Cas9 technology three ROS1 drug resistance-causing mutations: G2032R, L2026M and S1986Y. Such variants are located in different functional regions of the ROS1 kinase domain, thus conferring TKI resistance through distinct mechanisms. We then performed pharmacological assays in 2D and 3D to assess the cellular response of the mutant lines to crizotinib, entrectinib, lorlatinib, repotrectinib and ceritinib. In addition, immunoblotting assays were performed in 2D-treated cell lines to determine ROS1 phosphorylation and MAP kinase pathway activity. The area over the curve (AOC) defined by the normalized growth rate (NGR&#95;fit) dose-response curves was the variable used to quantify the cellular response towards TKIs., Results: Spheroids derived from ROS1 G2032R cells were significantly more resistant to repotrectinib (AOC fold change = - 7.33), lorlatinib (AOC fold change = - 6.17), ceritinib (AOC fold change = - 2.8) and entrectinib (AOC fold change = - 2.02) than wild type cells. The same cells cultured as a monolayer reflected the inefficacy of crizotinib (AOC fold change = - 2.35), entrectinib (AOC fold change = - 2.44) and ceritinib (AOC fold change = - 2.12) in targeting the ROS1 G2032R mutation. ROS1 L2026M cells showed also remarkable resistance both in monolayer and spheroid culture compared to wild type cells, particularly against repotrectinib (spheroid AOC fold change = - 2.19) and entrectinib (spheroid AOC fold change = - 1.98). ROS1 S1986Y cells were resistant only towards crizotinib in 2D (AOC fold change = - 1.86). Overall, spheroids showed an increased TKI sensitivity compared to 2D cultures, where the impact of each mutation that confers TKI resistance could be clearly distinguished. Western blotting assays qualitatively reflected the patterns of response towards TKI observed in 2D culture through the levels of phosphorylated-ROS1. However, we observed a dose-response increase of phosphorylated-Erk1/2, suggesting the involvement of the MAPK pathway in the mediation of apoptosis in HCC78 cells., Conclusion: In this study we knock-in for the first time in a ROS1 + patient-derived cell line, three different known resistance-causing mutations using CRISPR/Cas9 in the endogenous translocated ROS1 alleles. Pharmacological assays performed in 2D and 3D cell culture revealed that spheroids are more sensitive to TKIs than cells cultured as a monolayer. This direct comparison between two culture systems could be done thanks to the implementation of normalized growth rates (NGR) to uniformly quantify drug response between 2D and 3D cell culture. Overall, this study presents the added value of using spheroids and positions lorlatinib and repotrectinib as the most effective TKIs against the studied ROS1 resistance point mutations., (© 2024. The Author(s).)

Competing Interests: The author reports no conflicts of interest in the last 3 years.

Objectives: The aim of this study is to conduct a cost-utility analysis of the use of the antiviral nirmatrelvir/ritonavir, applied to a vaccinated Brazilian population against COVID-19, from the perspective of the Brazilian Public Health System (SUS)., Methods: A microsimulation model was created with individual-level data and daily cycles, with a 1-year time horizon, to compare the current scenario of standard care with a scenario in which nirmatrelvir/ritonavir is offered to the population. Adults of any age group that received ≥2 doses of the COVID-19 vaccine formed the investigated population. Direct medical costs of the outpatients and inpatients admitted to the ward or intensive care unit were included. The effectiveness of the model was measured in quality-adjusted life-years (QALYs)., Results: In all simulations, the use of nirmatrelvir/ritonavir resulted in incremental costs per patient of US dollar (USD)245.86 and incremental effectiveness of 0.009 QALY, over a year. The incremental cost-utility ratio was USD27 220.70/QALY. The relative risk of the vaccinated population was the factor that affected the outcome most, according to the univariate sensitivity analysis. The probabilistic sensitivity analysis resulted in 100% of the simulations being more costly and effective, but that only 4% of them were below the established cost-effectiveness threshold of USD24 000.00/QALY. In the scenario considering only the population over 60 years old and immunosuppressed (of any age), the incremental cost-utility ratio was USD7589.37/QALY., Conclusions: The use of nirmatrelvir/ritonavir in the treatment of COVID-19 in a vaccinated population was cost-effective only for immunosuppressed individuals and people over 60 years of age., Competing Interests: Author Disclosures Links to the individual disclosure forms provided by the authors are available here., (Copyright © 2023 International Society for Health Economics and Outcomes Research. Published by Elsevier Inc. All rights reserved.)

Objectives: To evaluate the cost-effectiveness of lorlatinib compared to 1 st generation anaplastic lymphoma kinase (ALK) TKI crizotinib, and 2 nd generation TKIs alectinib and brigatinib, for previously untreated patients with ALK+ advanced Non-Small Cell Lung Cancer (aNSCLC)., Methods: A partitioned survival model was locally adapted from a Greek payer perspective over a lifetime horizon. Clinical, safety and utility data were extracted from literature. Direct medical costs reflecting the year 2023 were included in the analysis (€). Model outcomes were patients' life years (LYs), quality-adjusted life years (QALYs), total costs and incremental cost-effectiveness ratios (ICERs)., Results: Total cost per patient with lorlatinib, alectinib, crizotinib, and brigatinib was estimated to be €188,205, €183,343, €75,028, and €145,454 respectively. Lorlatinib appeared to yield more LYs and QALYs gained versus alectinib, crizotinib, and brigatinib. Hence, lorlatinib resulted in ICERs of €4,315 per LY gained and €4,422 per QALY gained compared to alectinib, €34,032 per LY gained and €48,256 per QALY gained versus crizotinib and €16,587 per LY gained and €26,271 per QALY gained compared to brigatinib., Conclusion: Lorlatinib provides substantial clinical benefit and appears to be a cost - effective treatment option compared to 1 st and 2 nd generation TKIs for previously untreated patients with ALK+ aNCSLC in Greece.

Objective: The aim of the study was to evaluate the safety profile of nirmatrelvir-ritonavir (NMV-r) in real clinical practice and to analyse the clinical relevance of drug-drug interactions in the development of adverse events., Methods: Observational, retrospective study in which safety data of patients treated with NMV-r between April and July 2022 in an outpatient setting were evaluated. The duration of follow-up was 28 days and the number of adverse reactions reported, as well as whether they were managed on an outpatient basis or required health care, and the presence of renal and hepatic function impairment were assessed. Concomitant treatment was reviewed, identifying theoretical drug-drug interactions (TDDIs) whose severity was defined using the Lexi-interact classification., Results: The study included 146 patients. 82 (56.16%) were women, whose median age was 65 years (22-95). the number of TDDIs detected and maintained during treatment with NMV-r was 164, with the percentage of patients with at least 1 interaction being 62.33%. The median number of TDDIs per patient was 1 (0-5). At least 1 adverse event (AE) was reported in 18 patients (11.84%). 11 AEs were potentially related to any TDDI. 7 patients required contact with hospital assistance for AE management. 8 patients had impaired renal function and 2 had impaired liver function at 28 days. The main groups of drugs implicated in the occurrence of an AE were oral anticoagulants and calcium antagonists., Conclusions: Our results show a high number of TDDIs detected were detected between NMV-r and other drugs. This study provides greater knowledge of the drugs involved in such interactions and their potential relationship with the occurrence of adverse events., Competing Interests: Conflicts of interest None declared., (Copyright © 2023 Sociedad Española de Farmacia Hospitalaria (S.E.F.H). Publicado por Elsevier España, S.L.U. All rights reserved.)

Objective: The aim of the study was to evaluate the safety profile of nirmatrelvir-ritonavir (NMV-r) in real clinical practice and to analyze the clinical relevance of drug-drug interactions in the development of adverse events., Methods: Observational, retrospective study in which safety data of patients treated with NMV-r between April and July 2022 in an outpatient setting were evaluated. The duration of follow-up was 28 days and the number of adverse reactions reported, as well as whether they were managed on an outpatient basis or required health care, and the presence of renal and hepatic function impairment were assessed. Concomitant treatment was reviewed, identifying theoretical drug-drug interactions (TDDIs) whose severity was defined using the Lexi-interact classification., Results: The study included 146 patients, 82 (56,16%) were women, whose median age was 65 years (22-95). The number of TDDIs detected and maintained during treatment with NMV-r was 164, with the percentage of patients with at least one interaction being 62,33%. The median number of TDDIs per patient was 1 (0-5). At least 1 adverse event (AE) was reported in 18 patients (11,84%). Eleven AEs were potentially related to any TDDI. Seven patients required contact with hospital assistance for AE management. Eight patients had impaired renal function and 2 had impaired liver function at 28 days. The main groups of drugs implicated in the occurrence of an AE were oral anticoagulants and calcium antagonists., Conclusions: Our results show a high number of TDDIs detected were detected between NMV-r and other drugs. This study provides greater knowledge of the drugs involved in such interactions and their potential relationship with the occurrence of adverse events., (Copyright © 2023 Sociedad Española de Farmacia Hospitalaria (S.E.F.H). Publicado por Elsevier España, S.L.U. All rights reserved.)

Introduction: Lorlatinib is a potent, brain penetrant, next-generation ALK/ROS1 TKI, with high response rates and durable responses, including the brain. However, a significant drawback is the manifestation of neurocognitive adverse events (NCAEs). Despite being generally low-grade in severity, these NCAEs can be physically and mentally disabling. Extensive neurocognitive testing in this group of patients is lacking; therefore we conducted this study., Patients and Methods: This observational prospective study was conducted across 3 Dutch university hospitals. Patients with metastatic NSCLC with an ALK- or ROS1-rearrangement and having an indication to start lorlatinib in daily clinical practice were eligible. The primary endpoints were to identify changes in neurocognitive functioning, measured through neurocognitive assessment at intervals of 2 weeks and 2 months after starting lorlatinib, in comparison to baseline. As a secondary endpoint, the correlation between neurocognitive impairment and self-reported neurocognitive dysfunction was examined., Results: Between June 2019 and October 2022, 22 patients were included. Among the various neurocognitive tests administered, only the Hopkins Verbal Learning Test-Revised parts b and c demonstrated a significant and clinically relevant decrease in scoring 2 weeks post initiation of lorlatinib (P = .036 and P = .003, respectively). However, these returned to baseline at the 2-month evaluation. The questionnaires did not result in significantly different outcomes over time., Conclusion: Lorlatinib treatment did not result in a sustained and significant decline within any of the specified neurocognitive domains., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Lung transplant recipients (LTRs) have a higher risk of hospitalization and mortality due to COVID-19 compared with the immunocompetent population. The use of nirmatrelvir/ritonavir (NR), an effective oral treatment for COVID-19, is quite challenging due to its potent drug-drug interactions with immunosuppressants and azole antifungals. As there are few clinical reports of the use of NR in LTRs, we measured tacrolimus levels in patients receiving NR in our hospital to improve safety when prescribing NR., Methods: In total, 48 adult LTRs who received NR between November 19, 2022, and January 19, 2023, at China-Japan Friendship Hospital were retrospectively included and followed for 20 days after initiating NR. Tacrolimus was held at least 12 h before initiating NR and re-administered based on the trough levels after completing NR treatment. All concomitant medications, drug concentrations, laboratory results, and genotypes were recorded and analyzed., Results: Most patients showed stable tacrolimus trough levels despite high individual variability. Four patients exhibited supratherapeutic trough levels of tacrolimus (more than 15 ng/mL). Two patients who received 0.5 mg of tacrolimus during NR treatment had trough levels below 3.0 ng/mL. In addition, we found that in 13 patients, the trough levels were 130% of baseline after cessation of tacrolimus, and logistic regression revealed that increased trough level was significantly associated with age more than 60 years., Conclusions: NR can be safely used in LTRs with close monitoring of tacrolimus levels and appropriate dose adjustments. However, more attention should be paid to elderly patients, as NR may more severely affect their drug metabolism. Due to the limited sample size, further studies are needed to guide the optimal use of tacrolimus following treatment with NR and explore the risk factors significantly affecting the interactions between NR and tacrolimus., Competing Interests: Declaration of competing interest We declare that we have no financial and personal relationships with other people or organizations that can inappropriately influence our work, there is no professional or other personal interest of any nature or kind in any product, service and/or company that could be construed as influencing the position presented in, or the review of, the manuscript entitled., (Copyright © 2023. Published by Elsevier Ltd.)

Alectinib is the first-line therapy for anaplastic lymphoma kinase-positive non-small-cell lung cancer. Although some guidelines have recommended using other anaplastic lymphoma kinase inhibitors after alectinib failure, evidence for such regimens in patients who fail to respond to alectinib is limited. This study involved using administrative claims data from acute care hospitals in Japan. We extracted the data of 634 patients diagnosed with lung cancer between September 1, 2014, and January 31, 2023, who received alectinib treatment before treatment with another anaplastic lymphoma kinase inhibitor. We assessed distributions of patients according to their treatment sequencing and prognosis among three periods defined based on the initial marketing dates of lorlatinib and brigatinib. The type of anaplastic lymphoma kinase inhibitors after alectinib failure changed over time. In the most recent period, lorlatinib (58%) and brigatinib (40%) became predominant. Two-year overall survival improved over time (47%-84%), accompanied by an increased 2-year proportion of patients who continuously used anaplastic lymphoma kinase inhibitors after alectinib failure (13%-44%). The times to treatment discontinuation of the regimen between patients treated with lorlatinib and brigatinib were similar, with a hazard ratio of 1.02 (95% confidence interval, 0.64-1.64) in the period after marketing brigatinib. This study provides insights into the evolving treatment landscape for patients with anaplastic lymphoma kinase-positive non-small-cell lung cancer who experience failed alectinib treatment and highlights the need for further studies and data accumulation to determine the optimal treatment strategy., (© 2023 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Background: Coronavirus disease 2019 (COVID-19) is a respiratory virus that has afflicted millions of individuals in the United States. A few medications have been determined to be beneficial for outpatient treatment. The medications in use against mild-to-moderate COVID-19 in the outpatient setting during the study period are nirmatrelvir-ritonavir, remdesivir, molnupiravir, and bebtelovimab. Proper assessment and treatment of patients with mild-to-moderate COVID-19 in the outpatient setting is critical to reducing rates of disease progression and hospitalization., Objective: This study aimed to evaluate the appropriateness of the prescribing by internal medicine physicians for mild-to-moderate Coronavirus disease 2019 (COVID-19) infections based on the National Institutes of Health (NIH) guideline-directed COVID-19 outpatient treatment options., Methods: This is a retrospective chart review examining the outpatient treatment of mild-to-moderate COVID-19 by internal medicine physicians between February 2022 and August 2022. Patients were eligible if they were 18 years or older, had a positive home or polymerase chain reaction (PCR) test, completed a telehealth visit within 7 days of the positive test, and were prescribed either nirmatrelvir-ritonavir, remdesivir, molnupiravir, or bebtelovimab for COVID-19 treatment. The primary end point was the appropriateness of COVID-19 treatment in the outpatient setting based on NIH guidelines, patient characteristics, and prescribing information for the medications. The secondary end point was hospitalization within 30 days of initiation of outpatient COVID-19 treatment. The presence or absence of a clinical pharmacist consultation at the time of prescribing was recorded as a process measure., Results: A total of 376 encounters were assessed, of which 226 were included and analyzed. A total of 210 participants (93%) received nirmatrelvir-ritonavir. The remaining participants received molnupiravir or bebtelovimab. Overall, guideline-concordant treatment for mild-to-moderate COVID-19 was prescribed for 200 participants (88%). Among patient characteristics, only glomerular filtration rate (GFR) had a statistically significant difference between groups prescribed medication for the treatment of mild-to-moderate COVID-19. Fifty-six participants (25%) received clinical pharmacist consultation. Three participants were hospitalized for COVID-19 within 30 days of receiving an appropriately prescribed medication for treatment. Nirmatrelvir-ritonavir was the only medication potentially prescribed inappropriately due to lack of being renally dose adjusted and the extensive drug-drug interactions., Conclusion: Nirmatrelvir-ritonavir was the most prescribed medication for the treatment of mild-to-moderate COVID-19, consistent with its position as first-line therapy and widespread accessibility. The study results will inform future educational opportunities, such as in-service presentations and handouts, that may improve the prescribing of outpatient treatment for mild-to-moderate COVID-19 moving forward., Competing Interests: Disclosure The authors declare no relevant conflicts of interest or financial relationships., (Copyright © 2023 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.)

Objectives: Nirmatrelvir/ritonavir may cause a clinically relevant drug-drug interaction (DDI) with immunosuppressive drugs, such as tacrolimus, which may condition the use of this antiviral in transplant patients. We aimed to describe the management of this interaction., Methods: Descriptive study in which renal transplant patients in treatment with nirmatrelvir/ritonavir and tacrolimus were included. They suspended tacrolimus the day before starting the antiviral treatment, and the decision to restart it was made based on their tacrolimus blood levels. Main variables studied to measure this DDI were tacrolimus blood concentration, dose adjustment and serum creatinine., Results: Three patients were included. During the study, tacrolimus levels elevation did not have repercussion in the serum creatinine, that remained stable in all patients. No patient required hospitalisation or showed signs of rejection., Conclusions: Our experience provides further evidence that this interaction should not be a contraindication to treatment with nirmatrelvir/ritonavir, and can be managed with close monitoring of tacrolimus levels., Competing Interests: Competing interests: None declared., (© European Association of Hospital Pharmacists 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Feline infectious peritonitis (FIP) is a fatal feline disease, caused by a feline coronavirus (FCoV), namely feline infectious peritonitis virus (FIPV). We produced a baby hamster kidney 21 (BHK) cell line expressing a serotype I FCoV replicon RNA with a green fluorescent protein (GFP) reporter gene (BHK-F-Rep) and used it as an in vitro screening system to test different antiviral compounds. Two inhibitors of the FCoV main protease (M pro ), namely GC376 and Nirmatrelvir, as well as the nucleoside analog Remdesivir proved to be effective in inhibiting the replicon system. Different combinations of these compounds also proved to be potent inhibitors, having an additive effect when combined. Remdesivir, GC376, and Nirmatrelvir all have a 50% cytotoxic concentration (CC50) more than 200 times higher than their half-maximal inhibitory concentrations (IC50), making them important candidates for future in vivo studies as well as clinically implemented drug candidates. In addition, results were acquired with a virus infection system, where Felis catus whole fetus 4 (Fcwf-4) cells were infected with a previously described recombinant GFP-expressing FIPV (based on the laboratory-adapted serotype I FIPV strain Black) and treated with the most promising compounds. Results acquired with the replicon system were comparable to the results acquired with the virus infection system, demonstrating that we successfully implemented the FCoV replicon system for antiviral screening. We expect that this system will greatly facilitate future screens for anti-FIPV compounds and provide a non-infectious system to study and evaluate drug-resistant mutations that may emerge in the FIPV genome.IMPORTANCEFIPV is of great significance in the cat population around the world, causing 0.3%-1.4% of feline deaths in veterinary practices (2). As there are neither effective preventive measures nor approved treatment options available, there is an urgent need to identify antiviral drugs against FIPV. Our FCoV replicon system provides a valuable tool for drug discovery in vitro . Due to the lack of cell culture systems for serotype I FCoVs (the serotype most prevalent in the feline population) (2), a different system is needed to study these viruses. A viral replicon system is a valuable tool for studying FCoVs. Overall, our results demonstrate the utility of the serotype I feline coronavirus replicon system for antiviral screening as well as to study this virus in general. We propose several compounds representing promising candidates for future clinical trials and ultimately with the potential to save cats suffering from FIP., Competing Interests: The authors declare no conflict of interest.

Background: Current guidelines recommend using nirmatrelvir-ritonavir for coronavirus disease 2019 (COVID-19) treatment, but its potential drug interactions and contraindications limit its applicability in certain categories of patients. The aim of the study was to evaluate the real-world effectiveness of molnupiravir and nirmatrelvir-ritonavir in managing COVID-19 among hospitalized patients., Methods: We conducted a retrospective cohort study among hospitalized COVID-19 patients who received molnupiravir or nirmatrelvir-ritonavir and did not require baseline supplemental oxygen from February 2022 to January 2023. We compared the effectiveness of molnupiravir and nirmatrelvir-ritonavir with a focus on disease progression., Results: The study included 401 high-risk, hospitalized adult COVID-19 patients who received molnupiravir or nirmatrelvir-ritonavir. No significant difference was found in disease progression, the composite outcome of disease progression (4.0% vs. 1.4%, P = 0.782), and O 2 supplementation via nasal prong (21.8% vs. 14.8%, P = 0.115) between the patients treated with molnupiravir and those treated with nirmatrelvir-ritonavir. This finding was similar after 1:1 propensity-score matching. In the multivariate analysis, molnupiravir treatment was not significantly associated with progression to severe disease., Conclusion: In conclusion, our findings suggest that similar to nirmatrelvir-ritonavir, molnupiravir has a distinct potential role in COVID-19 treatment, transcending its current perceived status as only a secondary option., Competing Interests: The authors have no potential conflicts of interest to disclose., (© 2024 The Korean Academy of Medical Sciences.)

Objectives: Molnupiravir and nirmatrelvir-ritonavir were the first oral antiviral agents to demonstrate reduced hospitalization or death in patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), but patients with immunocompromised conditions were not well-represented. The objective of this study was to characterize and compare the clinical outcomes of US veterans with immunocompromised conditions prescribed oral antivirals with those who did not receive oral antivirals for mild-to-moderate SARS-CoV-2 active infection., Methods: This was a retrospective, observational, nationwide propensity-matched analysis of US veterans with immunocompromised conditions who developed documented SARS-CoV-2 infection. The primary outcome was the composite of any hospitalization or death within 30 days of diagnosis. Secondary outcomes included 30-day comparative rates of (1) any hospitalization, (2) death, (3) intensive care requirement, and (4) subset analyses of outcomes by oral antiviral used and vaccination status., Results: The composite primary outcome was significantly lower in patients receiving oral antiviral therapy compared with those who did not (23/390 [5.9%] vs 57/390 [14.6%]; odds ratio, 0.37; 95% confidence interval, .22-.61). This difference was driven largely by fewer deaths in the oral antiviral group (1/390 [0.3%] vs 19/390 [4.9%]; odds ratio, 0.05; 95% confidence interval, .007-.38). There was no significant difference in rate of intensive care requirement. The composite outcome was improved in vaccinated patients (completing the first series or first booster dose) who received oral antiviral agents compared with those who did not receive oral antiviral agents. Compared with those prescribed nirmatrelvir-ritonavir, patients given molnupiravir were older, had a higher incidence of cautions/contraindications, greater prevalence of tobacco use, and more cardiovascular complications., Conclusions: Use of molnupiravir or nirmatrelvir-ritonavir was associated with lower incidences of hospitalization or death within 30 days of diagnosis in US veterans with immunocompromised conditions, regardless of vaccination status. These findings support the use of either oral antiviral in this patient population., Competing Interests: Potential conflicts of interest. G. K. reports grants or contracts for serving as local principal investigator for 2 Cooperative Studies Program studies (funded by Veterans Health Administration) at Oklahoma City Veterans Affairs Healthcare System; a role as Board member of Northcare—nonprofit Mental health provider organization, Oklahoma City, OK. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (Published by Oxford University Press on behalf of Infectious Diseases Society of America 2023.)

Background: The ALTA-1 L trial and EXP-3B arm of NCT01970865 trial found that both brigatinib and lorlatinib showed durable and robust responses in treating ALK-positive non-small cell lung cancer (NSCLC) patients. However, brigatinib and lorlatinib treatments are costly and need indefinite administration until the disease progression. Thus, it remains uncertain whether using brigatinib followed by lorlatinib before chemotherapy is cost-effective compared to reserving these two drugs until progression after chemotherapy., Methods: We used a Markov model to assess clinical outcomes and healthcare costs of treating ALK-positive NSCLC individuals with brigatinib followed by lorlatinib before chemotherapy versus a strategy of reserving these drugs until progression after chemotherapy. Transition probabilities were estimated using parametric survival modeling based on multiple clinical trials. The drug acquisition costs, adverse events costs, administration costs were extracted from published studies before and publicly available data. We calculated lifetime direct healthcare costs, quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratios from the perspective of a United States payer., Results: Our base-case analysis indicated that the incremental cost-effectiveness ratios of using first-line brigatinib followed by lorlatinib compared with second-line brigatinib followed by lorlatinib is $-400,722.09/QALY which meant that second-line brigatinib followed by lorlatinib had less costs and better outcomes. Univariate sensitivity analysis indicated the results were most sensitive to the cost of brigatinib. Probability sensitivity analysis revealed that using brigatinib followed by lorlatinib before chemotherapy had a 0% probability of cost-effectiveness versus delaying these two drugs until progression after chemotherapy at a willingness-to-pay threshold of $150,000 per QALY. Sensitivity analyses conducted revealed the robustness of this result, as incremental cost-effectiveness ratios never exceeded the willingness-to-pay threshold., Conclusion: Using brigatinib as first-line treatment followed by lorlatinib for ALK-positive NSCLC may not be cost-effective given current pricing from the perspective of a United States payer. Delaying brigatinib followed by lorlatinib until subsequent lines of treatment may be a reasonable strategy that could limit healthcare costs without affecting clinical outcomes. More mature data are needed to better estimate cost-effectiveness in this setting., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as potential conflicts of interest., (Copyright © 2024 Liu, Huo and Chen.)

Multiple tyrosine kinase inhibitors (TKIs) are often developed for the same indication. However, their relative overall efficacy is frequently incompletely understood and they may harbor unrecognized targets that cooperate with the intended target. We compared several ROS1 TKIs for inhibition of ROS1-fusion-positive lung cancer cell viability, ROS1 autophosphorylation and kinase activity, which indicated disproportionately higher cellular potency of one TKI, lorlatinib. Quantitative chemical and phosphoproteomics across four ROS1 TKIs and differential network analysis revealed that lorlatinib uniquely impacted focal adhesion signaling. Functional validation using pharmacological probes, RNA interference, and CRISPR-Cas9 knockout uncovered a polypharmacology mechanism of lorlatinib by dual targeting ROS1 and PYK2, which form a multiprotein complex with SRC. Rational multi-targeting of this complex by combining lorlatinib with SRC inhibitors exhibited pronounced synergy. Taken together, we show that systems pharmacology-based differential network analysis can dissect mixed canonical/non-canonical polypharmacology mechanisms across multiple TKIs enabling the design of rational drug combinations., Competing Interests: Declaration of interests R.C.D. is an employee and shareholder of Rain Oncology and reports licensing fees from Voronoi, Takeda, Loxo@Lilly, Foundation Medicine, Histocyte, Black Diamond, and ThermoFisher. JMK reports support from Bristol-Myers Squibb on an unrelated project. E.B.H. serves in a consulting or advisory role to Amgen, Ellipses Pharma, Janssen Oncology, Janssen Research & Development and Revolution Medicines; reports research funding (paid to his institution) from AstraZeneca, Genentech, Incyte, Janssen, Novartis, Revolution Medicines and Spectrum Pharmaceuticals; and reports patents, royalties or other intellectual property from ProteinProtein Interactions as Biomarkers Patent., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

This study aimed to explore the effectiveness and safety of azvudine, nirmatrelvir/ritonavir, and molnupiravir in adult patients with mild-to-moderate COVID-19. This retrospective cohort study included patients with mild-to-moderate COVID-19 (asymptomatic, mild, and common types) at the First Hospital of Changsha (Hunan Province, China) between March and November 2022. Eligible patients were classified into the azvudine, nirmatrelvir/ritonavir, or molnupiravir groups according to the antiviral agents they received. The outcomes were the times to nucleic acid negative conversion (NANC). This study included 157 patients treated with azvudine (n = 66), molnupiravir (n = 66), or nirmatrelvir/ritonavir (n = 25). There were no statistically significant differences in the time from diagnosis to NANC among the azvudine, molnupiravir, and nirmatrelvir/ritonavir groups [median, 9 (95% CI 9-11) vs. 11 (95% CI 10-12) vs. 9 (95% CI 8-12) days, P = 0.15], time from administration to NANC [median, 9 (95% CI 8-10) vs. 10 (95% CI 9.48-11) vs. 8.708 (95% CI 7.51-11) days, P = 0.50], or hospital stay [median, 11 (95% CI 11-13) vs. 13 (95% CI 12-14) vs. 12 (95% CI 10-14) days, P = 0.14], even after adjustment for sex, age, COVID-19 type, comorbidities, Ct level, time from diagnosis to antiviral treatment, and number of symptoms. The cumulative NANC rates in the azvudine, molnupiravir, and nirmatrelvir/ritonavir groups were 15.2%/12.3%/16.0% at day 5 (P = 0.858), 34.8%/21.5%/32.0% at day 7 (P = 0.226), 66.7%/52.3%/60.0% at 10 days (P = 0.246), and 86.4%/86.2%/80.0% at day 14 (P = 0.721). No serious adverse events were reported. Azvudine may be comparable to nirmatrelvir/ritonavir and molnupiravir in adult patients with mild-to-moderate COVID-19 regarding time to NANC, hospital stay, and AEs., (© 2024. The Author(s).)

Objectives: To compare the efficacy, safety and effects on quality of life of different ALK-inhibitors for global and Asian patients with advanced ALK-positive non-small-cell lung cancer (NSCLC)., Methods: The included RCTs were identified through a systematic search of PubMed, EMBASE, Cochrane Library, Clinical Trials.gov, and major cancer conferences. The assessment of progression-free survival (PFS), intracranial PFS, overall survival (OS), and patient-reported outcomes (PROs) was carried out using restricted mean survival time (RMST) model, fractional polynomial model and Royston-Parmar model. Time-invariant hazard ratio (HR) models were also used to validate and supplement the primary analysis. Objective response rate (ORR) and adverse events with any grade, grade 3-5 were assessed through a Bayesian network meta-analysis. The primary measures for OS, PFS, and PROs were HR and RMST. The odds ratio was the metric for evaluating safety, ORR, 12-month PFS rate, 24-month OS rate, and the 12-month non-deterioration rate of PROs. Subgroup analyses based on patient characteristics were performed., Results: A total of fourteen studies (ten for first-line, four for second-line) consisting of nine treatments (chemotherapy, crizotinib, alectinib [600mg BID], low-dose alectinib [300mg BID], brigatinib, ceritinib, ensartinib, envonalkib, and lorlatinib) were included. In the first-line setting, alectinib showed a significant advantage over crizotinib and had the longest OS among all ALK-inhibitors. Compared to crizotinib, lorlatinib had the best efficacy regarding PFS for global patients, followed closely by alectinib and brigatinib. For Asian patients, alectinib significantly improved PFS compared to other treatments. In second-line, alectinib had the highest PFS for patients pretreated with crizotinib, followed by brigatinib, ceritinib and chemotherapy. Alectinib, irrespective of the dose, was the safest first-line option, whereas lorlatinib, brigatinib, and ceritinib showed poorer safety profiles. Alectinib was also the safest ALK-inhibitor for crizotinib-resistant patients. Brigatinib had the best performance in terms of PROs., Conclusions: Considering both efficacy and safety, alectinib appears to be the preferable treatment in first-line and second-line, particularly for Asian patients., (© 2024. The Author(s).)

Nirmatrelvir-ritonavir (NR) was approved to treat SARS-CoV-2 positive outpatients at high risk of progression to severe disease, based on a randomized trial in unvaccinated patients. Effectiveness in vaccinated patients and against Omicron has not yet been confirmed by clinical trial data, but a recent meta-analysis suggested good real-world effectiveness based on 12 studies. We updated this meta-analysis by searching Medline and Embase databases for studies assessing effectiveness of NR on mortality, hospitalization, composite outcome of hospitalization and/or death, and progression to severe disease, published between October 1, 2022 and May 22, 2023. Random effects meta-analysis and subgroup analysis for vaccinated patients was performed. A total of 32 studies were included in the meta-analysis. Pooled RR for the effect of NR on mortality, hospitalization, hospitalization and/or mortality, and progression to severe disease were 0.36 (95% confidence interval [CI]: 0.25-0.52), 0.43 (CI: 0.37-0.51), 0.52 (CI: 0.45-0.61) and 0.54 (CI: 0.41-0.73), respectively. A subgroup analysis on vaccinated patients indicated lower effectiveness of NR on mortality (RR: 0.55, CI: 0.45-0.68), but similar effectiveness for hospitalization, hospitalization and/or mortality, or progression to severe disease (RR: 0.52, 0.58, and 0.66, respectively). This updated meta-analysis robustly confirms the protective effects of NR on severe COVID-19 outcomes., (© 2024 Belgian Health Care Knowledge Centre. Journal of Medical Virology published by Wiley Periodicals LLC.)

Insulin replacement therapy is essential for the management of diabetes. However, despite the relative success of this therapeutic strategy, there is still a need to improve glycaemic control and the overall quality of life of patients. This need has driven research into orally available, glucose-responsive and rapid-acting insulins. A key consideration during analogue development is formulation stability, which can be improved via the replacement of insulin's A6-A11 disulfide bond with stable mimetics. Unfortunately, analogues such as these require extensive chemical synthesis to incorporate the nonnative cross-links, which is not a scalable synthetic approach. To address this issue, we demonstrate proof of principle for the semisynthesis of insulin analogues bearing nonnative A6-A11 cystine isosteres. The key feature of our synthetic strategy involves the use of several biosynthetically derived peptide precursors which can be produced at scale cost-effectively and a small, chemically synthesised A6-A11 macrocyclic lactam fragment. Although the assembled A6-A11 lactam insulin possesses poor biological activity in vitro, our synthetic strategy can be applied to other disulfide mimetics that have been shown to improve thermal stability without significantly affecting activity and structure. Moreover, we envisage that this new semisynthetic approach will underpin a new generation of hyperstable proteomimetics., (© 2023 The Authors. Journal of Peptide Science published by European Peptide Society and John Wiley & Sons Ltd.)

We evaluated the population-level benefits of expanding treatment with the antiviral drug Paxlovid (nirmatrelvir/ritonavir) in the United States for SARS-CoV-2 Omicron variant infections. Using a multiscale mathematical model, we found that treating 20% of symptomatic case-patients with Paxlovid over a period of 300 days beginning in January 2022 resulted in life and cost savings. In a low-transmission scenario (effective reproduction number of 1.2), this approach could avert 0.28 million (95% CI 0.03-0.59 million) hospitalizations and save US $56.95 billion (95% CI US $2.62-$122.63 billion). In a higher transmission scenario (effective reproduction number of 3), the benefits increase, potentially preventing 0.85 million (95% CI 0.36-1.38 million) hospitalizations and saving US $170.17 billion (95% CI US $60.49-$286.14 billion). Our findings suggest that timely and widespread use of Paxlovid could be an effective and economical approach to mitigate the effects of COVID-19.