Antiviral Therapy最新文献

{"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":"28 4","pages":"13596535231189643"},"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":"28 3","pages":"13596535231174774"},"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":"28 3","pages":"13596535231172878"},"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":"28 3","pages":"13596535231182505"},"PeriodicalIF":1.3,"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":"28 3","pages":"13596535231174273"},"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}

{"title":"Fanconi syndrome, diabetes insipidus, and acute kidney injury due to tenofovir disoproxil fumarate: A case report.","authors":"Nthabiseng Zilwa,&nbsp;Onalethata Mpejane,&nbsp;Golam Mehboob,&nbsp;Sajan Gill,&nbsp;Thomas Kalinoski","doi":"10.1177/13596535231186727","DOIUrl":"10.1177/13596535231186727","url":null,"abstract":"<p><strong>Background: </strong>Tenofovir disoproxil fumarate is widely used in Botswana as part of the first-line antiretroviral regimen in the 'Treat All' strategy implemented in 2016 by the Ministry of Health. Its use has been associated with several uncommon adverse renal effects, though rarely all in conjunction or without the combined use of protease inhibitors.</p><p><strong>Case presentation: </strong>A 49-year-old woman living with HIV whose viral load is suppressed on tenofovir disoproxil fumarate, lamivudine, and dolutegravir presented with 1 day of generalized weakness and myalgia causing an inability to ambulate. This was associated with nausea and vomiting and profound fatigue. She was found to have an acute kidney injury, non-anion-gap metabolic acidosis, hypernatremia, hypokalemia, and hypophosphatemia. Urinalysis revealed pyuria with white blood cell casts, glucosuria, and proteinuria. The diagnosis was made of tenofovir-induced nephrotoxicity. The tenofovir was discontinued, and the patient was initiated on intravenous fluids and electrolyte and bicarbonate supplementation with improvement in her symptoms and laboratory values.</p><p><strong>Conclusions: </strong>This report suggests the possibility of severe tenofovir-induced nephrotoxicity with combined acute kidney injury, Fanconi syndrome, and nephrogenic diabetes insipidus in the absence of other provoking factors such as use with protease inhibitors or advanced HIV disease, chronic kidney disease, and age. With its wide use in Botswana and other countries, health-care providers should have a high index of suspicion for tenofovir-induced nephrotoxicity for HIV patients on tenofovir with deranged renal function tests and electrolytes.</p>","PeriodicalId":8364,"journal":{"name":"Antiviral Therapy","volume":"28 3","pages":"13596535231186727"},"PeriodicalIF":1.2,"publicationDate":"2023-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9695435","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":"Letter to the editor on use of antibodies from convalescent sera in the treatment of moderate and severe Covid-19 infection.","authors":"Sarah B Nahhal,&nbsp;Bassem Awada,&nbsp;Joe-David Azzo,&nbsp;Rayyan Wazzi-Mkahal,&nbsp;Souha Kanj,&nbsp;Zeina A Kanafani","doi":"10.1177/13596535231186866","DOIUrl":"10.1177/13596535231186866","url":null,"abstract":"Convalescent plasma (CP) is a form of passive immunization that is used for disease prevention by transferring specific antibodies from a recovered patient to another patient with the same infection. It has been studied in the treatment of several viral infections with major conflicting results, including the Ebola virus, SARS-CoV1, and MERS-CoV. More recently, CP usage has been studied widely in the treatment of SARS-CoV2. Similar to previous studies in different outbreaks, the results have been inconsistent. In the recovery and CONCOR-1 trials, there was no difference in mortality nor clinical status at day 28 after CP infusion. On the other hand, Joyner et al. and Libster et al. showed that early infusion of high-titer CP may help in preventing clinical deterioration in mild Covid19 infection. Early in the pandemic and due to limited available therapeutic options for Covid-19 infection in Lebanon, we elected to study the efficacy of high-titer CP in moderate Covid-19 infections. A prospective and retrospective cohort study was conducted at the American University of Beirut Medical Center (AUBMC) over 14 months. It included all patients above 18 years presenting to AUBMC for moderate to severe Covid-19 infection. We excluded pregnant women and patients with a predicted survival of less than 2 days. Patients who received CP treatment (cases) in addition to standard therapy were compared to those who received standard therapy alone. The medical records for patients in both groups were reviewed and data related to demographics, medical comorbidities, symptoms upon presentation, the severity of infection on admission, laboratory findings, and treatment received were extracted. The clinical progress and laboratory data were recorded before and after receiving CP. Data were entered into a database using SPSS 29.0 (SPSS Inc, Chicago, IL). Bivariable analysis was conducted to examine the association between demographic and clinical variables with various outcome measures. The chi-square test and the independent samples t-test were used for categorical and continuous variables, respectively. A p-value of less than .05 was considered significant. We included 23 patients who received CP as cases and 46 patients as controls. Themean age in the cases group (63.4 ± 13.1 years) was more than that in the control group (60.5 ± 15.6). 52% of each group were males and 48% were females. The two groups had no significant difference in baseline demographics and medical comorbidities. Regarding the other Covid-19-related therapeutic options, corticosteroidsweremore","PeriodicalId":8364,"journal":{"name":"Antiviral Therapy","volume":"28 3","pages":"13596535231186866"},"PeriodicalIF":1.2,"publicationDate":"2023-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9751711","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":"Lipid and glucose abnormalities and associated factors among children living with HIV in Asia.","authors":"Tulathip Suwanlerk, Dhanushi Rupasinghe, Watsamon Jantarabenjakul, Vu T An, Jeremy L Ross, Azar Kariminia, Nguyen Van Lam, Aarti Kinikar, Pradthana Ounchanum, Thanyawee Puthanakit, Nik K Nik Yusoff, Pagakrong Lumbiganon, Kulkanya Chokephaibulkit, Do C Viet, Tavitiya Sudjaritruk, Fong S Moy, Dewi K Wati, Thahira J Mohamed, Revathy Nallusamy, Nagalingeswaran Kumarasamy, Vohith Khol, Truong H Khanh, Nia Kurniati","doi":"10.1177/13596535231170751","DOIUrl":"10.1177/13596535231170751","url":null,"abstract":"<p><strong>Background: </strong>Children living with HIV (CLHIV) on prolonged antiretroviral therapy (ART) are at risk for lipid and glucose abnormalities. Prevalence and associated factors were assessed in a multicentre, Asian longitudinal paediatric cohort.</p><p><strong>Methods: </strong>CLHIV were considered to have lipid or glucose abnormalities if they had total cholesterol ≥200 mg/dL, high-density lipoprotein (HDL) ≤35 mg/dL, low-density lipoprotein (LDL) ≥100 mg/dL, triglycerides (TG) ≥110 mg/dL, or fasting glucose >110 mg/dL. Factors associated with lipid and glucose abnormalities were assessed by logistic regression.</p><p><strong>Results: </strong>Of 951 CLHIV, 52% were male with a median age of 8.0 (interquartile range [IQR] 5.0-12.0) years at ART start and 15.0 (IQR 12.0-18.0) years at their last clinic visit. 89% acquired HIV perinatally, and 30% had ever used protease inhibitors (PIs). Overall, 225 (24%) had hypercholesterolemia, 105 (27%) low HDL, 213 (58%) high LDL, 369 (54%) hypertriglyceridemia, and 130 (17%) hyperglycemia. Hypercholesterolemia was more likely among females (versus males, aOR 1.93, 95% CI 1.40-2.67). Current PIs use was associated with hypercholesterolemia (current use: aOR 1.54, 95% CI 1.09-2.20); low HDL (current use: aOR 3.16, 95% CI 1.94-5.15; prior use: aOR 10.55, 95% CI 2.53-43.95); hypertriglyceridemia (current use: aOR 3.90, 95% CI 2.65-5.74; prior use: aOR 2.89, 95% CI 1.31-6.39); high LDL (current use: aOR 1.74, 95% CI 1.09-2.76); and hyperglycemia (prior use: aOR 2.43, 95% CI 1.42-4.18).</p><p><strong>Conclusion: </strong>More than half and one-fifth of CLHIV have dyslipidemia and hyperglycemia, respectively. Routine paediatric HIV care should include metabolic monitoring. The association between PIs use and dyslipidemia emphasizes the importance of rapidly transitioning to integrase inhibitor-containing regimens.</p>","PeriodicalId":8364,"journal":{"name":"Antiviral Therapy","volume":"28 2","pages":"13596535231170751"},"PeriodicalIF":1.3,"publicationDate":"2023-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10825667/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9972626","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Population pharmacokinetic/pharmacodynamic models of JNJ-64794964, a toll-like receptor 7 agonist, in healthy adult participants.","authors":"Liviawati S Wu, Yue Hu, Edward J Gane, Leen Slaets, An De Creus, Yanhua Ding, Junqi Niu, Christian Schwabe, Nele Goeyvaerts, Zhongnan Xu, Dandan Huo, Marianne Tuefferd, Inge Verbrugge, Pieter Van Remoortere, Ullrich Schwertschlag, Joris Vandenbossche","doi":"10.1177/13596535231151626","DOIUrl":"10.1177/13596535231151626","url":null,"abstract":"<p><strong>Background: </strong>JNJ-4964 is a TLR7 agonist, which, via a type I interferon (IFN)-dependent mechanism, may enhance host immunity suppressed by persistent exposure to hepatitis B antigens in chronic hepatitis B.</p><p><strong>Methods: </strong>PK and PD data were pooled from 2 studies involving 90 participants (<i>n</i> = 74 JNJ-4964, dose range 0.2-1.8 mg; <i>n</i> = 16 placebo) in a fasted state. Food effects on PK were studied in 24 participants (1.2 or 1.25 mg). A population PK model and PK/PD models were developed to characterize the effect of JNJ-4964 plasma levels on the time course of IFN-α, IFN-γ-inducible protein 10 (IP-10 or CXCL10), IFN-stimulated gene 15 (<i>ISG15</i>), neopterin and lymphocytes following single and weekly dosing in healthy adults. Covariate effects, circadian rhythms and negative feedback were incorporated in the models.</p><p><strong>Results: </strong>A 3-compartment linear PK model with transit absorption adequately described JNJ-4964 PK. Bioavailability was 44.2% in fed state relative to fasted conditions. Indirect response models with maximum effect (E_max) stimulation on production rate constant (k_in) described IFN-α, IP-10, <i>ISG15</i> and neopterin, while a precursor-dependent indirect response model with inhibitory effect described the transient lymphocyte reduction. E_max, EC₅₀ and γ (steepness) estimates varied according to PD markers, with EC₅₀ displaying substantial between-subject variability. Female and Asian race exhibited lower EC₅₀, suggesting higher responsiveness.</p><p><strong>Conclusions: </strong>PK/PD models well characterized the time course of immune system markers in healthy adults. Our results supported sex and race as covariates on JNJ-4964 responsiveness, as well as circadian rhythms and negative feedback as homeostatic mechanisms that are relevant in TLR7-induced type I IFN responses.</p>","PeriodicalId":8364,"journal":{"name":"Antiviral Therapy","volume":"28 1","pages":"13596535231151626"},"PeriodicalIF":1.2,"publicationDate":"2023-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9149225","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":"Pharmacokinetics of zanamivir in critically ill patients undergoing continuous venovenous hemofiltration.","authors":"André Wieringa,&nbsp;Peter Gj Ter Horst,&nbsp;GertJan Hj Wagenvoort,&nbsp;Birgit Cp Koch,&nbsp;Jasper J Haringman","doi":"10.1177/13596535221150746","DOIUrl":"https://doi.org/10.1177/13596535221150746","url":null,"abstract":"<p><strong>Background: </strong>Limited data exist for dosing of zanamivir in the setting of CVVH in the intensive care unit (ICU). Our objective is to report the pharmacokinetics and sieving coefficient (S_v) of zanamivir in patients receiving continuous venovenous hemofiltration (CVVH).</p><p><strong>Methods: </strong>In this prospective observational study, patients of ≥18 years admitted to the ICU with a life-threatening Influenza A or B infection, treated with zanamivir i.v. undergoing CVVH were included. Patients received a zanamivir loading dose of 600 mg i.v., 12 h later followed by maintenance dosages two times daily according to the treating physician. Per patient, nine CFT plasma and nine ultrafiltrate samples were drawn on day 2 of treatment and analysed with a validated HPLC-MS/MS method.</p><p><strong>Results: </strong>Four patients were included in the study. The zanamivir elimination half-life was prolonged with 5.6-9.9 h, compared to patients with normal renal function. A S_v of approximately 1.0 was identified, with unrestricted transport of zanamivir to the ultrafiltrate.</p><p><strong>Conclusions: </strong>Zanamivir is well cleared by CVVH. In absence of the possibility for therapeutic drug monitoring, the ultrafiltration rate seems as a good surrogate parameter to estimate the CL_CVVH and may help guide the dosing of zanamivir.</p>","PeriodicalId":8364,"journal":{"name":"Antiviral Therapy","volume":"28 1","pages":"13596535221150746"},"PeriodicalIF":1.2,"publicationDate":"2023-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10756347","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}