Antiviral Therapy最新文献

{"title":"Waitlist-controlled trial of an online intervention to address mental health among older people living with HIV.","authors":"Jeff Berko, Peter Mazonson, Duncan Short, Maile Karris, Lynsay Ehui, Cassidy A Gutner, Frank Spinelli, Andrew Zolopa","doi":"10.1177/13596535231216311","DOIUrl":"10.1177/13596535231216311","url":null,"abstract":"<p><p><b>Background:</b> Older people living with HIV (PLWH) often experience elevated levels of depression, anxiety, and loneliness.<b>Methods:</b> This waitlist-controlled trial examined the effectiveness of online audio mindfulness lessons in impacting these feelings among older PLWH.<b>Results:</b> Among 214 participants, the mean (SD) age was 60.4 (5.9) years, 89% were male, and 69% were white. After 25 days, the intervention group showed significant improvements versus the waitlist control group in symptoms of depression (20.3% improvement, <i>p</i> < .01) and symptoms of anxiety (22.4% improvement, <i>p</i> = .03), but not in loneliness as measured by a Daily Diary (12.9% improvement, <i>p</i> = .07) or the 3-Item Loneliness Scale (4.8% improvement, <i>p</i> = .27). Secondary analyses among participants with elevated baseline symptoms of depression showed a 26.3% improvement (<i>p</i> < .01), with a moderate effect size (Hedge's g = 0.69). Similarly, those with elevated baseline symptoms of anxiety showed a 25.6% improvement (<i>p</i> < .01), a moderate effect size (g = 0.54), while those with moderate or severely elevated loneliness showed an 18.9% improvement in daily loneliness (<i>p</i> < .01), a moderate effect size (g = 0.55).<b>Conclusion:</b> This waitlist-controlled trial is the first to show that a series of brief, online audio mindfulness lessons improves mental health outcomes among older PLWH. For many patients, this intervention may offer relief that is both accessible and affordable.</p>","PeriodicalId":8364,"journal":{"name":"Antiviral Therapy","volume":null,"pages":null},"PeriodicalIF":1.2,"publicationDate":"2023-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138457571","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Andrographolide inhibits infectious bronchitis virus-induced apoptosis, pyroptosis, and inflammation.","authors":"Jiachen Shen, Qiuchi Xu, Lu Chen, Xinyu Chang, Ruiting Shen, Zhenhua Zhao, Lifei Zhu, Yifei Wu, Xiaolin Hou","doi":"10.1177/13596535231207499","DOIUrl":"10.1177/13596535231207499","url":null,"abstract":"<p><strong>Background: </strong>Avian infectious bronchitis virus (IBV), a coronavirus, causes a huge economic loss to the poultry industry. Andrographolide (APL) is a compound with a variety of pharmacological properties, including antiviral and anti-inflammatory effects. In this study, APL was evaluated for antiviral activity by its anti-apoptotic, anti-pyroptosis, and anti-inflammatory effects.</p><p><strong>Methods: </strong>The cytotoxicity of APL was determined by the MTT method. We investigated the therapeutic impact of APL on IBV through a plate assay. We explored that APL inhibited IBV-induced apoptosis, pyroptosis, and inflammation in HD11 cells by RT-qPCR and immunofluorescence. Also, it was verified in the clinical chicken embryo trial.</p><p><strong>Results: </strong>We found that APL down-regulated apoptosis-related genes Caspase-3, Caspase-8, Caspase-9, Bax, Bid, and Bak, down-regulated pyroptosis gene DFNA5, and down-regulated inflammation-related genes (NF-κB, NLRP3, iNOS, TNF-α, and IL-1β). In addition, APL reduced the reactive oxygen species (ROS) production in cells. Finally, clinical trials showed that APL inhibited IBV-induced apoptosis, pyroptosis, and inflammation, as well as reduced the mortality and malformation of chicken embryos.</p><p><strong>Conclusions: </strong>In this study, we delved into the antiviral properties of APL in the context of chicken macrophage (HD11) infection with IBV. Our findings confirm that andrographolide effectively inhibits apoptosis, pyroptosis, and inflammation by IBV infection. Furthermore, this inhibition was verified on chicken embryos in vivo. This inhibition suggests a substantial potential for APL as a therapeutic agent to mitigate the harmful effects of IBV on host cells.</p>","PeriodicalId":8364,"journal":{"name":"Antiviral Therapy","volume":null,"pages":null},"PeriodicalIF":1.2,"publicationDate":"2023-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41231919","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Computer-assisted drug discovery of potential natural inhibitors of the SARS-CoV-2 RNA-dependent RNA polymerase through a multi-phase <i>in silico</i> approach.","authors":"Eslam B Elkaeed,&nbsp;Bshra A Alsfouk,&nbsp;Tuqa H Ibrahim,&nbsp;Reem K Arafa,&nbsp;Hazem Elkady,&nbsp;Ibrahim M Ibrahim,&nbsp;Ibrahim H Eissa,&nbsp;Ahmed M Metwaly","doi":"10.1177/13596535231199838","DOIUrl":"https://doi.org/10.1177/13596535231199838","url":null,"abstract":"<p><strong>Background: </strong>The COVID-19 pandemic has led to significant loss of life and economic disruption worldwide. Currently, there are limited effective treatments available for this disease. SARS-CoV-2 RNA-dependent RNA polymerase (SARS-CoV-2 RdRp) has been identified as a potential target for drug development against COVID-19. Natural products have been shown to possess antiviral properties, making them a promising source for developing drugs against SARS-CoV-2.</p><p><strong>Objectives: </strong>The objective of this study is to identify the most effective natural inhibitors of SARS-CoV-2 RdRp among a set of 4924 African natural products using a multi-phase <i>in silico</i> approach.</p><p><strong>Methods: </strong>The study utilized remdesivir (RTP), the co-crystallized ligand of RdRp, as a starting point to select compounds that have the most similar chemical structures among the examined set of compounds. Molecular fingerprints and structure similarity studies were carried out in the first part of the study. The second part of the study included molecular docking against SARS-CoV-2 RdRp (PDB ID: 7BV2) and Molecular Dynamics (MD) simulations including the calculation of RMSD, RMSF, Rg, SASA, hydrogen bonding, and PLIP. Moreover, the calculations of Molecular mechanics with generalised Born and surface area solvation (MM-GBSA) Lennard-Jones and Columbic electrostatic interaction energies have been conducted. Additionally, <i>in silico</i> ADMET and toxicity studies were performed to examine the drug likeness degrees of the selected compounds.</p><p><strong>Results: </strong>Eight compounds were identified as the most effective natural inhibitors of SARS-CoV-2 RdRp. These compounds are kaempferol 3-galactoside, kaempferol 3-<i>O</i>-<i>β</i>-D-glucopyranoside, mangiferin methyl ether, luteolin 7-<i>O</i>-<i>β</i>-D-glucopyranoside, quercetin-<i>O</i>-<i>β</i>-D-3-glucopyranoside, 1-methoxy-3-indolylmethyl glucosinolate, naringenin, and asphodelin A 4'-<i>O</i>-<i>β</i>-D-glucopyranoside.</p><p><strong>Conclusion: </strong>The results of this study provide valuable information for the development of natural product-based drugs against COVID-19. However, the elected compounds should be further studied <i>in vitro</i> and <i>in vivo</i> to confirm their efficacy in treating COVID-19.</p>","PeriodicalId":8364,"journal":{"name":"Antiviral Therapy","volume":null,"pages":null},"PeriodicalIF":1.2,"publicationDate":"2023-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41189581","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Subacute thyroiditis following COVID-19 vaccination: Case presentation.","authors":"Aleksandra Z Tomic, Sonja S Zafirovic, Zoran M Gluvic, Vladimir S Samardzic, Mirjana T Macvanin, Maja Lj Radunovic, Esma R Isenovic","doi":"10.1177/13596535231208831","DOIUrl":"10.1177/13596535231208831","url":null,"abstract":"<p><p><b>Background:</b> Subacute thyroiditis (SAT) is an organ-specific disease that various drugs, including COVID-19 vaccines, can trigger. COVID-19 infection has been associated with thyroid gland damage and disease SARS-CoV-2 direct action, euthyroid sick syndrome, and immune-mediated mechanisms are all potential mechanisms of thyroid damage. It denotes thyroid gland inflammation, most commonly of viral origin, and belongs to the transitory, self-limiting thyroid gland diseases group, causing complications in approximately 15% of patients in the form of permanent hypothyroidism. Some authors say SAT is the most common thyroid disease associated with COVID-19.<b>Purpose:</b> The occurrence of SAT many weeks after administering the second COVID-19 vaccine is rare and has limited documentation in academic literature. This study aims to present the occurrence of SAT after administering the COVID-19 vaccine. We present the case of a 37-year-old man who developed SAT 23 days after receiving the second dose of Pfizer BioNTech's COVID-19 mRNA vaccine.<b>Research design and study sample:</b> Due to neck pain and an elevated body temperature (up to 38.2°C), a 37-year-old male subject presented for examination 23 days after receiving the second Pfizer BioNTech mRNA vaccine against SARS-CoV-2 viral infection. The patient denied ever having an autoimmune disease or any other disease. Painful neck palpation and a firm, slightly enlarged thyroid gland with no surrounding lymphadenopathy were identified during the exam. The heart rate was 104 beats per minute. All of the remaining physical findings were normal.<b>Data collection and/or Analysis:</b> Data collected during the disease are integral to the medical record.<b>Results:</b> Hematology and biochemistry analyses at the initial and follow-up visits revealed minor leukocytosis, normocytic anaemia, and thrombocytosis, followed by a mild increase in lactate dehydrogenase and decreased iron levels. The patient's thyroid function and morphology had recovered entirely from post-vaccine SAT.<b>Conclusions</b>: Results from this study emphasise the need for healthcare professionals to promptly report any case of SAT related to COVID-19 vaccination. Further investigation is warranted to understand the immunopathogenesis of COVID-19-associated thyroiditis and the impact of COVID-19 immunization on this condition.</p>","PeriodicalId":8364,"journal":{"name":"Antiviral Therapy","volume":null,"pages":null},"PeriodicalIF":1.2,"publicationDate":"2023-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"49673766","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"HIV drug resistance in the era of contemporary antiretroviral therapy: A clinical perspective.","authors":"Andrew Carr,&nbsp;Nicola E Mackie,&nbsp;Roger Paredes,&nbsp;Kiat Ruxrungtham","doi":"10.1177/13596535231201162","DOIUrl":"10.1177/13596535231201162","url":null,"abstract":"<p><p>Contemporary antiretroviral therapy (ART) regimens have high barriers to the development of drug resistance. However, resistance to earlier antiretrovirals and uncommon cases of resistance to contemporary ART illustrate the continued need for good clinical management of HIV drug resistance. Here, we describe HIV drug-resistance mechanisms, the interaction of HIV drug-resistant mutations and the patterns of drug resistance to contemporary ART. We then provide guidance on the management of HIV drug resistance, including how to limit the development of resistance and manage virologic failure that is complicated by resistance. To complement this, links to resources and treatment guidelines are provided that can assist with the interpretation of HIV drug resistance test results and optimal ART selection in the clinic.</p>","PeriodicalId":8364,"journal":{"name":"Antiviral Therapy","volume":null,"pages":null},"PeriodicalIF":1.2,"publicationDate":"2023-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41103709","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hepatitis C virus/Hepatitis B virus coinfection: Current prospectives.","authors":"Quratulain Maqsood,&nbsp;Aleena Sumrin,&nbsp;Maryam Iqbal,&nbsp;Saima Younas,&nbsp;Nazim Hussain,&nbsp;Muhammada Mahnoor,&nbsp;Abdul Wajid","doi":"10.1177/13596535231189643","DOIUrl":"10.1177/13596535231189643","url":null,"abstract":"<p><p>In endemic areas, hepatitis C virus (HCV)/hepatitis B virus (HBV) coinfection is common, and patients with coinfection have a higher risk of developing liver disease such as hepatocellular carcinoma, liver fibrosis and cirrhosis. In such cases, HCV predominates, and HBV replication is suppressed by HCV. HCV core proteins and interferons that are activated by HCV are responsible for the suppression of HBV. Immunosuppression is also seen in patients with HCV and HBV coinfections. A decrease in HCV-neutralizing antibody response and circulation of Th1-like Tfh cells is observed in patients with HCV and HBV coinfection. Both viruses interacted in the liver, and treatment of HCV/HBV coinfection is genotype-based and complex due to the interaction of both viruses. In HCV-dominant cases, direct-acting antiviral drugs and peg interferon plus ribavirin are used for the treatment, with continuous monitoring of AST and ALT. HBV-dominant cases are less common and are treated with peg interferon and nucleoside nucleotide analogues with monitoring of AST and ALT. The SVR rate in HCV-HBV coinfection is higher than that in monoinfection when treated with direct-acting antiviral drugs. But there is a risk of reactivation of HBV during and after therapy. The rate of reactivation is lower in patients treated with direct-acting antiviral drugs as compared to those treated with peg interferon plus ribavirin. Biomarkers of HBV such as HBcrAg, HBV DNA and HBVpg RNA are not effective in the prediction of HBV reactivation; only the hepatitis B surface antigen titre can be used as a biomarker for HBV reactivation. HCV can also be reactive, but this is found in very rare cases in which HBV is present and is treated first.</p>","PeriodicalId":8364,"journal":{"name":"Antiviral Therapy","volume":null,"pages":null},"PeriodicalIF":1.2,"publicationDate":"2023-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10247376","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The evolution of clinical study design in heavily treatment-experienced persons with HIV: A critical review.","authors":"Judith A Aberg,&nbsp;Anthony Mills,&nbsp;Santiago Moreno,&nbsp;Jill Slater,&nbsp;Manyu Prakash,&nbsp;Andrew Clark","doi":"10.1177/13596535231174774","DOIUrl":"https://doi.org/10.1177/13596535231174774","url":null,"abstract":"<p><p>Heavily treatment-experienced (HTE) persons with HIV have limited options for antiretroviral therapy and face many challenges, complicating their disease management. There is an ongoing need for new antiretrovirals and treatment strategies for this population. We reviewed the study designs, baseline characteristics, and results of clinical trials that enrolled HTE persons with HIV. A PubMed literature search retrieved articles published between 1995 and 2020, which were grouped by trial start date (1995-2009, <i>N</i> = 89; 2010-2014, <i>N</i> = 3; 2015-2020, <i>N</i> = 2). Clinical trials in HTE participants markedly declined post-2010. Participant characteristics and study designs showed changes in trends over time. As treatment strategies for HTE persons with HIV progress, we must look beyond virologic suppression to consider the broader needs of this complex heterogeneous population.</p>","PeriodicalId":8364,"journal":{"name":"Antiviral Therapy","volume":null,"pages":null},"PeriodicalIF":1.2,"publicationDate":"2023-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9617460","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A single, oral dose of the TLR7 agonist JNJ-64794964 induces transcriptomic and phenotypic changes in peripheral immune cells in healthy adults.","authors":"Wim Pierson,&nbsp;Marianne Tuefferd,&nbsp;Florence Herschke,&nbsp;Leen Slaets,&nbsp;Marjolein Crabbe,&nbsp;Dorien Verstappen,&nbsp;Steffi De Pelsmaeker,&nbsp;Ian Strickland,&nbsp;Edward J Gane,&nbsp;Christian Schwabe,&nbsp;Yingjie Zhang,&nbsp;Peter Meerts,&nbsp;Joris Vandenbossche,&nbsp;Pieter Van Remoortere,&nbsp;Inge Verbrugge,&nbsp;An De Creus","doi":"10.1177/13596535231172878","DOIUrl":"https://doi.org/10.1177/13596535231172878","url":null,"abstract":"<p><strong>Background: </strong>Chronic hepatitis B (CHB) is responsible for major disease burden worldwide. However, the number of available therapies is limited; cure remains an elusive goal. JNJ-64794964 (JNJ-4964) is an oral toll-like receptor-7 (TLR7) agonist being evaluated for the treatment of CHB. Here, we investigated the capacity of JNJ-4964 to induce transcriptomic and immune cell changes in peripheral blood in healthy volunteers.</p><p><strong>Methods: </strong>Peripheral blood was collected in the JNJ-4964 first-in-human phase 1 trial at multiple time points to assess transcriptomics and changes in frequency and phenotype of peripheral-blood mononuclear cells. Correlation of changes to JNJ-4964 exposure (C_max) and changes in cytokine levels (C-X-C motif chemokine ligand 10 [CXCL10] and interferon alpha [IFN-α]) were evaluated.</p><p><strong>Results: </strong>Fifty-nine genes, mainly interferon-stimulated genes, were up-regulated between 6 hours and 5 days after JNJ-4964 administration. JNJ-4964 increased frequencies of CD69, CD134, CD137, and/or CD253-expressing natural killer (NK) cells, indicative of NK cell activation. These changes correlated with C_max, increase of CXCL10, and induction of IFN-α and were observed at IFN-α levels that are associated with no/acceptable flu-like adverse events. JNJ-4964 administration resulted in increased frequencies of CD86-expressing B cells, indicative of B-cell activation. These changes were predominantly observed at high IFN-α levels, which are associated with flu-like adverse events.</p><p><strong>Conclusions: </strong>JNJ-4964 administration led to changes in transcriptional profiles and immune cell activation phenotype, particularly for NK cells and B cells. Together, these changes could represent a set of biomarkers for the characterization of the immune response in CHB patients receiving TLR7 agonists.</p>","PeriodicalId":8364,"journal":{"name":"Antiviral Therapy","volume":null,"pages":null},"PeriodicalIF":1.2,"publicationDate":"2023-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9615555","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Feminizing hormone therapy in a Canadian cohort of transgender women with and without HIV.","authors":"Ian Armstrong, Ashley Lacombe-Duncan, Mostafa Shokoohi, Yasmeen Persad, Alice Tseng, Raymond Fung, Angela Underhill, Pierre Côté, Nimâ Machouf, Adrien Saucier, Brenda Varriano, Monica Brundage, Reilly Jones, Thea Weisdorf, John Goodhew, John MacLeod, Mona Loutfy","doi":"10.1177/13596535231182505","DOIUrl":"10.1177/13596535231182505","url":null,"abstract":"<p><strong>Background: </strong>Potential bidirectional drug-drug interactions between feminizing hormone therapy (FHT) and antiretroviral therapy (ART) are of concern for trans women with HIV and their healthcare providers. This study aimed to characterize patterns of FHT and ART among trans women with HIV and to compare serum hormone levels to trans women without HIV.</p><p><strong>Methods: </strong>Charts of trans women were reviewed at seven HIV primary care or endocrinology clinics in Toronto and Montreal from 2018 to 2019. ART regimens, FHT use, serum estradiol, and serum testosterone levels were compared on the basis of HIV status (positive, negative, missing/unknown).</p><p><strong>Results: </strong>Of 1495 trans women, there were 86 trans women with HIV, of whom 79 (91.8%) were on ART. ART regimens were most commonly integrase inhibitor-based (67.4%), many boosted with ritonavir or cobicistat (45.3%). Fewer (71.8%) trans women with HIV were prescribed FHT, compared to those without HIV (88.4%) and those with missing/unknown status (90.2%, <i>p <</i> 0.001). Among trans women on FHT with recorded serum estradiol (<i>n</i> = 1153), there was no statistical difference in serum estradiol between those with HIV (median: 203 pmol/L, IQR: 95.5, 417.5) and those with negative (200 mol/L [113, 407]) or missing/unknown HIV status (227 pmol/L [127.5, 384.5) (<i>p =</i> 0.633). Serum testosterone concentrations were also similar between groups.</p><p><strong>Conclusions: </strong>In this cohort, trans women with HIV were prescribed FHT less often than trans women with negative or unknown HIV status. There was no difference in serum estradiol or testosterone levels of trans women on FHT regardless of HIV status, providing reassurance regarding potential drug-drug interactions between FHT and ART.</p>","PeriodicalId":8364,"journal":{"name":"Antiviral Therapy","volume":null,"pages":null},"PeriodicalIF":1.2,"publicationDate":"2023-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9629295","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genotypic and phenotypic characterization of influenza A viral variants in study participants treated with pimodivir in the phase 2b TOPAZ study.","authors":"Johan Vingerhoets,&nbsp;Ilse Van Dromme,&nbsp;Wilbert van Duijnhoven,&nbsp;David Anderson,&nbsp;Sandra De Meyer,&nbsp;Lorant Leopold","doi":"10.1177/13596535231174273","DOIUrl":"https://doi.org/10.1177/13596535231174273","url":null,"abstract":"<p><strong>Background: </strong>Pimodivir is a first-in-class polymerase basic protein 2 (PB2) subunit inhibitor of the influenza A polymerase complex. The randomized double-blinded placebo-controlled phase 2b TOPAZ study demonstrated antiviral activity and safety of twice daily pimodivir alone (300 mg, 600 mg) or in combination with oseltamivir (pimodivir 600 mg, oseltamivir 75 mg) in adult study participants with acute uncomplicated influenza A. The detailed genotypic and phenotypic characterization of viral variants observed in this study are reported.</p><p><strong>Methods: </strong>Population sequencing of PB2 and neuraminidase genes, and phenotypic susceptibility testing, were performed using baseline and last virus-positive post-baseline nasal swab samples.</p><p><strong>Results: </strong>Sequencing of baseline samples in 206 of 223 (92.4%) randomized study participants with confirmed influenza A infection identified no polymorphisms at any predefined PB2 positions of interest for pimodivir and no phenotypic reduced susceptibility to pimodivir was observed. Post-baseline sequencing data for 105/223 (47.1%) participants identified emergence of PB2 mutations at amino acid positions of interest in 10 (9.5%) participants (pimodivir 300 mg: <i>n</i> = 3; 600 mg: <i>n</i> = 6; combination: <i>n</i> = 1; placebo: <i>n</i> = 0) and included positions S324, F325, S337, K376, T378, and N510. These emerging mutations were typically associated with decreased pimodivir susceptibility, but not viral breakthrough. No reduced phenotypic susceptibility was observed in the one (1.8%) participant with emerging PB2 mutations from the pimodivir plus oseltamivir group.</p><p><strong>Conclusions: </strong>Participants with acute uncomplicated influenza A treated with pimodivir in the TOPAZ study infrequently developed reduced susceptibility to pimodivir and combining pimodivir with oseltamivir further decreased the risk of reduced susceptibility development.</p>","PeriodicalId":8364,"journal":{"name":"Antiviral Therapy","volume":null,"pages":null},"PeriodicalIF":1.2,"publicationDate":"2023-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9617475","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}