國家衛生研究院 NHRI:Item 3990099045/15766

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Title:	Suboptimal response to combination therapy with tixagevimab/cilgavimab and remdesivir for persistent SARS-CoV-2 infections in immunocompromised patients
Authors:	Wu, TY;Chen, PY;Wang, JT;Liu, WD;Chen, YC;Chang, SC
Contributors:	National Institute of Infectious Diseases and Vaccinology
Abstract:	Persistent severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection remains clinically challenging in immunocompromised patients. The ongoing viral replication may increase morbidity and mortality by causing prolonged respiratory tract infection and illness, and delaying chemotherapy in patients with haematological malignancies. The optimal management for persistent SARS-CoV-2 infection is currently unknown. An additional 5 days of IV remdesivir and/or subcutaneous injection of anti-SARS-CoV-2 monoclonal antibodies (mAbs), tixagevimab/cilgavimab at a dose of 300/300 mg, could be utilized as salvage therapy for immunocompromised patients with a protracted course of COVID-19 when tixagevimab/cilgavimab remains active against the predominant SARS-CoV-2 variants, including BA.5 and BA.2.75, circulating in Taiwan. 1,2 The aim of this study was to evaluate the effectiveness and safety profile of dual combination with tixagevimab/cilgavimab and remdesivir in immunocompromised patients with persistent SARS-CoV-2 infections. This observational study included immunocompromised adults with persistent SARS-CoV-2 infections, defined by compatible respiratory symptoms and persistently high viral load in respiratory specimens with Ct values of <25 determined by RT– PCR for ≥14 days after at least one course of antiviral therapy. Combination therapy was administered after a multidisciplinary approach by infectious disease specialists and primary care physicians, shared decision-making with the patient and his/her family, and formal application to and then approved by Taiwan Centers for Disease Control. 1 All participants received dual combinations according to the following protocol: tixagevimab/cilgavimab 300/300 mg once, followed by a 5 day treatment course of remdesivir. Respiratory specimens for SARS-CoV-2 RT–PCR were collected at the time of diagnosis and then weekly or biweekly. The primary and secondary endpoints were virological response at Day 14 and combined clinical and virological response at Day 30 after completion of combination therapy, respectively. Virological response was defined as Ct values of ≥30 from two consecutive respiratory specimens at least 24 h apart, and clinical response was defined as a decrease of WHO Clinical Progression Scale (WHO-CPS) ≥ 1. This study was approved by the institution research ethics committee (202304006RINA). From October 2022 through to March 2023, 27 immunocompromised patients with persistent SARS-CoV-2 infections were enrolled (Table 1). The majority (n = 22) in our cohort had a history of haematological malignancy, mainly non-Hodgkin’s lymphoma (n = 15). Two-thirds (18/27) received B-cell depletion therapy within 12 months before COVID-19 onset. Our patients had received a median of 2 (IQR, 1–2) antiviral courses prior to initiation of dual combinations. At the time of dual combinations, the median WHO-CPS score was 5 (IQR, 4–6), greater than that at baseline [2 (2–4)]. Among patients tested, over half (10/18) had an anti-spike IgG level of <250.0 U/mL, and two-thirds (8/12) had a negative result of anti-nucleocapsid IgG. Median interval between initial diagnosis of COVID-19 and receipt of dual combination was 33 days (IQR, 19–91). After dual combinations, the rate of virological response at Day 14 was 33% (n = 9). All of them had sustained virological response at Day 30, while only five had clinical response with a median WHO-CPS score reduction of 2 (IQR, 1–3), reflecting that respiratory symptoms are partly attributed to persistent inflammation rather than infection. Hence, the rate of combined clinical and virological response at Day 30 was 18.5%. Prior receipt of B-cell depletion therapy was associated with worse virological response at Day 14 (P = 0.03) and showed a similar association with combined clinical and virological response at Day 30. No serious adverse events occurred. Our findings are consistent with previous studies showing that combination therapy with antivirals and anti-SARS-CoV-2 mAbs in immunocompromised COVID-19 patients may be beneficial for persistent/relapsing SARS-CoV-2 infections. 3,4 However, the virological and clinical responses in our study were probably limited by two reasons. First, we didn’t extend the treatment courses of antiviral agents. Some studies have reported successful treatment of persistent infections by extending antiviral courses to 10–20 days. 3–6 Second, several studies have shown successful treatment for persistent infections by nirmatrelvir/ritonavir- containing regimens, 3,5,6 7 probably due to the most potent activity in viral load reduction by nirmatrelvir/ritonavir compared with all other antivirals. Besides, no severe adverse drug event was reported in our study, confirming an acceptable safety profile of short-course combination therapy. Strengths of the current study included this series being one of the largest cohorts of immunocompromised patients receiving combination therapy for persistent COVID-19 to date and is followed by the local standard of care with uniform administration of dual combinations. There are several limitations in our study. Without genomic characterizations of sequential SARS-CoV-2 isolates, we can’t exclude the possibility of spike mutations conferring reduced activities to mAbs during viral intrahost evolutions, as well as acquired remdesivir resistance before dual combinations in our patients. Our data suggested that virological response to dual combination therapy for persistent SARS-CoV-2 infections was suboptimal, especially among those receiving B-cell depletion therapy within 12 months before COVID-19. Further randomized controlled trials are warranted to define the appropriate treatment strategy among this vulnerable population.
Date:	2024-05
Relation:	Journal of Antimicrobial Chemotherapy. 2024 May;79(5):1196-1200.
Link to:	http://dx.doi.org/10.1093/jac/dkae082
JIF/Ranking 2023:	http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=NHRI&SrcApp=NHRI_IR&KeyISSN=0305-7453&DestApp=IC2JCR
Cited Times(WOS):	https://www.webofscience.com/wos/woscc/full-record/WOS:001192137000001
Cited Times(Scopus):	https://www.scopus.com/inward/record.url?partnerID=HzOxMe3b&scp=85192113341
Appears in Collections:	[Yee-Chun Chen] Periodical Articles

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