Catherine Wolfe, Iulia Gabriela Ionescu, Marie-Hélène Mayrand, François Coutlée, Chantal Sauvageau
Background The province of Quebec (Canada) has had a school-based Human Papillomavirus (HPV) vaccination program with high coverage since 2008, with more than 90% of girls having received at least one quadrivalent vaccine (4vHPV) dose by age 15. In 2018, Quebec was the first jurisdiction to switch to a mixed schedule (nonavalent+bivalent), and as such wanted to evaluate it. However, when devising an evaluation strategy for new vaccine schedules, the presence of herd effect needs to be ascertained. With this in mind, this study aimed to measure HPV prevalence among unvaccinated 16-20-year-old sexually active men. Methods In 2020-2022, men were recruited from schools and online across the province of Quebec. Participants completed an online questionnaire and provided a self-collected penile swab (surface) for HPV detection and genotyping (Anyplex™ II-HPV28 Detection assay). Risk factors associated with HPV positivity were assessed. Vaccination status (unvaccinated) was verified through the Quebec Vaccination Registry. Results Overall, 369 participants provided a sample suitable for HPV testing. HPV prevalence was 18.4% (95%CI:14.6-22.8). Only two participants harbored a 4vHPV-targeted genotype (0.5%; 95%CI:0.1-1.9), both reporting sexual contact with men. In multivariate analysis, age, greater number of lifetime sexual partners and history of other sexually transmitted infections were independently associated with positivity for at least one HPV genotype. Conclusion The low 4vHPV-targeted genotypes prevalence (˂1%) among unvaccinated men of the same age as women vaccinated with 4vHPV suggests a strong herd immunity among young adults in Quebec. Evaluation of schedule changes will have to take this finding into account.
{"title":"Prevalence of Human Papillomavirus Genotypes in Unvaccinated 16-20-Year-Old Males in Quebec, Canada","authors":"Catherine Wolfe, Iulia Gabriela Ionescu, Marie-Hélène Mayrand, François Coutlée, Chantal Sauvageau","doi":"10.1093/infdis/jiaf094","DOIUrl":"https://doi.org/10.1093/infdis/jiaf094","url":null,"abstract":"Background The province of Quebec (Canada) has had a school-based Human Papillomavirus (HPV) vaccination program with high coverage since 2008, with more than 90% of girls having received at least one quadrivalent vaccine (4vHPV) dose by age 15. In 2018, Quebec was the first jurisdiction to switch to a mixed schedule (nonavalent+bivalent), and as such wanted to evaluate it. However, when devising an evaluation strategy for new vaccine schedules, the presence of herd effect needs to be ascertained. With this in mind, this study aimed to measure HPV prevalence among unvaccinated 16-20-year-old sexually active men. Methods In 2020-2022, men were recruited from schools and online across the province of Quebec. Participants completed an online questionnaire and provided a self-collected penile swab (surface) for HPV detection and genotyping (Anyplex™ II-HPV28 Detection assay). Risk factors associated with HPV positivity were assessed. Vaccination status (unvaccinated) was verified through the Quebec Vaccination Registry. Results Overall, 369 participants provided a sample suitable for HPV testing. HPV prevalence was 18.4% (95%CI:14.6-22.8). Only two participants harbored a 4vHPV-targeted genotype (0.5%; 95%CI:0.1-1.9), both reporting sexual contact with men. In multivariate analysis, age, greater number of lifetime sexual partners and history of other sexually transmitted infections were independently associated with positivity for at least one HPV genotype. Conclusion The low 4vHPV-targeted genotypes prevalence (˂1%) among unvaccinated men of the same age as women vaccinated with 4vHPV suggests a strong herd immunity among young adults in Quebec. Evaluation of schedule changes will have to take this finding into account.","PeriodicalId":501010,"journal":{"name":"The Journal of Infectious Diseases","volume":"82 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-02-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143470735","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Dylan M Johnson, Karla A Fenton, Natalie Dobias, Thomas W Geisbert, Robert W Cross
Chapare virus (CHAPV) is an emerging arenavirus first discovered in Bolivia. Clinical cases have a high case fatality rate and a concerning capacity for person-to-person spread. Animal models of CHHF are needed to study pathogenesis and development of medical counter measures. Here, we present a narrowly focused study describing lethal infection of strain 13 guinea pigs with CHAPV. Animals challenged with CHAPV had progressive weight loss, lymphocytopenia, neutropenia, thrombocytopenia, hepatitis, vascular leakage, and gastrointestinal hemorrhage, resulting in uniform lethality between 7- and 16-days following challenge. This work lays the foundation for development of a small animal model of CHAPV infection.
{"title":"Natural History of Chapare Virus Infection in Strain 13 Guinea Pigs","authors":"Dylan M Johnson, Karla A Fenton, Natalie Dobias, Thomas W Geisbert, Robert W Cross","doi":"10.1093/infdis/jiaf081","DOIUrl":"https://doi.org/10.1093/infdis/jiaf081","url":null,"abstract":"Chapare virus (CHAPV) is an emerging arenavirus first discovered in Bolivia. Clinical cases have a high case fatality rate and a concerning capacity for person-to-person spread. Animal models of CHHF are needed to study pathogenesis and development of medical counter measures. Here, we present a narrowly focused study describing lethal infection of strain 13 guinea pigs with CHAPV. Animals challenged with CHAPV had progressive weight loss, lymphocytopenia, neutropenia, thrombocytopenia, hepatitis, vascular leakage, and gastrointestinal hemorrhage, resulting in uniform lethality between 7- and 16-days following challenge. This work lays the foundation for development of a small animal model of CHAPV infection.","PeriodicalId":501010,"journal":{"name":"The Journal of Infectious Diseases","volume":"3 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143462822","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Background Individuals who do not match any specific stage in the natural history of chronic hepatitis B are classified into the grey-zone, and appropriate management for these patients remains unclear. This study aimed to develop and validate a non-invasive model to identify grey-zone patients requiring antiviral therapy (AVT). Methods We retrospectively collected data on 200 grey-zone patients not requiring AVT (according to assessment by non-invasive parameters from 2010 to 2023 in six hospitals) and randomised them into development (n=140) and validation (n=60) cohorts. Univariable and multivariable regression analyses were performed to identify independent variables for establishing a nomogram to predict the probability of requiring AVT by liver biopsy, which was assessed using the area under the receiver operating characteristic curve (AUC), calibration plot analysis and decision curve analysis. Results Seventy-eight patients (n=39%) were identified as requiring AVT. Age [odds ratio(OR) 1.06, 95% confidence interval(CI) 1.01–1.11], alanine aminotransferase (OR 2.43, 95%CI 1.08–5.59), lymphocyte percentage (OR 6.43, 95%CI 1.23–33.64), platelet count (OR 0.99, 95%CI 0.98–0.1.00) and international normalised ratio per (0.01) (OR 0.99, 95%CI 0.98–0.1.00) were identified as independent variables for constructing the nomogram, which showed good discriminability (development dataset: AUC=0.755; validation dataset: AUC=0.707), calibration and clinical applicability. Patients with nomogram scores >197 and ≤132 were considered to have a high and low probability of needing AVT, respectively. Conclusions Grey-zone patients requiring AVT should be identified, and the model developed here is a promising tool. Trial registration ClinicalTrials.gov, NCT06041022
{"title":"A Model to Identify Grey-Zone Patients with Chronic Hepatitis B Requiring Antiviral Therapy: A Multicentre, Retrospective Study","authors":"Xue-Yan Yang, Xi-Dong Li, Bai-Yun Wu, Qiao Yang, Yu-Bao Zheng, Ming-Hua Zheng, Yin-Ping Wu, Hang-Yu Ma, Jing Zuo, Ruo-Xi Jia, Yue Yu, Ling-Yun Xu, Yu-Xin Tian, Qi An, Tao Zhang, Ying-Li He, Yu Shi, Yu-Chen Fan","doi":"10.1093/infdis/jiaf070","DOIUrl":"https://doi.org/10.1093/infdis/jiaf070","url":null,"abstract":"Background Individuals who do not match any specific stage in the natural history of chronic hepatitis B are classified into the grey-zone, and appropriate management for these patients remains unclear. This study aimed to develop and validate a non-invasive model to identify grey-zone patients requiring antiviral therapy (AVT). Methods We retrospectively collected data on 200 grey-zone patients not requiring AVT (according to assessment by non-invasive parameters from 2010 to 2023 in six hospitals) and randomised them into development (n=140) and validation (n=60) cohorts. Univariable and multivariable regression analyses were performed to identify independent variables for establishing a nomogram to predict the probability of requiring AVT by liver biopsy, which was assessed using the area under the receiver operating characteristic curve (AUC), calibration plot analysis and decision curve analysis. Results Seventy-eight patients (n=39%) were identified as requiring AVT. Age [odds ratio(OR) 1.06, 95% confidence interval(CI) 1.01–1.11], alanine aminotransferase (OR 2.43, 95%CI 1.08–5.59), lymphocyte percentage (OR 6.43, 95%CI 1.23–33.64), platelet count (OR 0.99, 95%CI 0.98–0.1.00) and international normalised ratio per (0.01) (OR 0.99, 95%CI 0.98–0.1.00) were identified as independent variables for constructing the nomogram, which showed good discriminability (development dataset: AUC=0.755; validation dataset: AUC=0.707), calibration and clinical applicability. Patients with nomogram scores >197 and ≤132 were considered to have a high and low probability of needing AVT, respectively. Conclusions Grey-zone patients requiring AVT should be identified, and the model developed here is a promising tool. Trial registration ClinicalTrials.gov, NCT06041022","PeriodicalId":501010,"journal":{"name":"The Journal of Infectious Diseases","volume":"49 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143434943","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Felicia C Chow, Paddy Kafeero, Patrick Muhumuza, Maria Nakimbugwe, Anthony Ssemaganda, Colman Tayebwa, Elana Farrell, Margaret Wilson, Payam Nahid, Rada Savic, Fiona Cresswell, Freddie M Kibengo
Background Tuberculous meningitis (TBM)-related deaths occur early, often within weeks after initiation of treatment. Enhanced treatment early in the disease course with agents that effectively penetrate the central nervous system may improve outcomes in TBM. Methods We conducted a phase 2, open-label, randomized trial in Masaka, Uganda to assess the safety and tolerability of linezolid 1200 mg versus no linezolid with high (35 mg/kg/day) or standard-dose (10 mg/kg/day) rifampin for 4 weeks in participants with definite or suspected TBM. The primary endpoint was any >grade 3 adverse event during the interventional period. Secondary endpoints included overall survival and functional independence adjusted for TBM disease grade. Results We randomized 40 participants (98% with HIV). One-fourth had microbiologically-confirmed TBM. Nearly 75% had moderate to severe disease (Medical Research Council grades II and III). No significant difference in >grade 3 adverse event-free survival was observed across the 4 treatment arms (p=0.18), or by linezolid (p=0.97) or rifampin (p=0.46) group. More favorable overall survival (OR 0.28 for death at 12 weeks, p=0.10; OR 0.43 at 24 weeks, p=0.24) and functional outcome [OR 2.22 for lower modified Rankin Scale score (i.e., less disability) at 12 weeks, p=0.18; OR 2.00 at 24 weeks, p=0.24) were observed in the linezolid group. Conclusions The addition of a short course of linezolid to treat predominantly moderate to severe TBM in adults with HIV did not introduce excess toxicity. Our findings add to growing evidence that linezolid is a safe and acceptable treatment for TBM that merits further investigation in larger multi-site trials.
{"title":"Safety and Tolerability of a Short Course of Linezolid for the Treatment of Predominantly Moderate to Severe Tuberculous Meningitis in Adults with HIV","authors":"Felicia C Chow, Paddy Kafeero, Patrick Muhumuza, Maria Nakimbugwe, Anthony Ssemaganda, Colman Tayebwa, Elana Farrell, Margaret Wilson, Payam Nahid, Rada Savic, Fiona Cresswell, Freddie M Kibengo","doi":"10.1093/infdis/jiaf089","DOIUrl":"https://doi.org/10.1093/infdis/jiaf089","url":null,"abstract":"Background Tuberculous meningitis (TBM)-related deaths occur early, often within weeks after initiation of treatment. Enhanced treatment early in the disease course with agents that effectively penetrate the central nervous system may improve outcomes in TBM. Methods We conducted a phase 2, open-label, randomized trial in Masaka, Uganda to assess the safety and tolerability of linezolid 1200 mg versus no linezolid with high (35 mg/kg/day) or standard-dose (10 mg/kg/day) rifampin for 4 weeks in participants with definite or suspected TBM. The primary endpoint was any >grade 3 adverse event during the interventional period. Secondary endpoints included overall survival and functional independence adjusted for TBM disease grade. Results We randomized 40 participants (98% with HIV). One-fourth had microbiologically-confirmed TBM. Nearly 75% had moderate to severe disease (Medical Research Council grades II and III). No significant difference in >grade 3 adverse event-free survival was observed across the 4 treatment arms (p=0.18), or by linezolid (p=0.97) or rifampin (p=0.46) group. More favorable overall survival (OR 0.28 for death at 12 weeks, p=0.10; OR 0.43 at 24 weeks, p=0.24) and functional outcome [OR 2.22 for lower modified Rankin Scale score (i.e., less disability) at 12 weeks, p=0.18; OR 2.00 at 24 weeks, p=0.24) were observed in the linezolid group. Conclusions The addition of a short course of linezolid to treat predominantly moderate to severe TBM in adults with HIV did not introduce excess toxicity. Our findings add to growing evidence that linezolid is a safe and acceptable treatment for TBM that merits further investigation in larger multi-site trials.","PeriodicalId":501010,"journal":{"name":"The Journal of Infectious Diseases","volume":"24 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143434964","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Jolein Gyonne Elise Laumen, Vu N Hieu, Pham H Nhung, Koen Vandelannoote, Nguyen Thi Tam, Nguyen T Trang, Nguyen T N Diep, Thomas Kesteman, Rogier H van Doorn, Tran M Chau, Paul C Adamson
Ceftriaxone resistance in Neisseria gonorrhoeae is an escalating global health concern, threatening the efficacy of empiric treatment. In the Asia-Pacific region, a rapid surge in ceftriaxone resistance has been observed, primarily associated with the penA-60.001 allele. This study, conducted in Hanoi, Vietnam between 2023 and 2024, analyzed 352 N. gonorrhoeae isolates and found a 27% prevalence of ceftriaxone resistance. Whole-genome sequencing identified that resistance was predominantly driven by the mosaic penA-237.001 allele, with a smaller contribution from penA-60.001. The high prevalence of resistance and the emergence of new alleles underscore the urgent threat to ceftriaxone as an empiric treatment option.
{"title":"High prevalence of ceftriaxone-resistant Neisseria gonorrhoeae in Hanoi, Vietnam, 2023-2024","authors":"Jolein Gyonne Elise Laumen, Vu N Hieu, Pham H Nhung, Koen Vandelannoote, Nguyen Thi Tam, Nguyen T Trang, Nguyen T N Diep, Thomas Kesteman, Rogier H van Doorn, Tran M Chau, Paul C Adamson","doi":"10.1093/infdis/jiaf071","DOIUrl":"https://doi.org/10.1093/infdis/jiaf071","url":null,"abstract":"Ceftriaxone resistance in Neisseria gonorrhoeae is an escalating global health concern, threatening the efficacy of empiric treatment. In the Asia-Pacific region, a rapid surge in ceftriaxone resistance has been observed, primarily associated with the penA-60.001 allele. This study, conducted in Hanoi, Vietnam between 2023 and 2024, analyzed 352 N. gonorrhoeae isolates and found a 27% prevalence of ceftriaxone resistance. Whole-genome sequencing identified that resistance was predominantly driven by the mosaic penA-237.001 allele, with a smaller contribution from penA-60.001. The high prevalence of resistance and the emergence of new alleles underscore the urgent threat to ceftriaxone as an empiric treatment option.","PeriodicalId":501010,"journal":{"name":"The Journal of Infectious Diseases","volume":"63 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143401266","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Lilliam Ambroggio, Todd A Florin, Kayla Williamson, Grace Bosma, Brandie D Wagner, Larisa Yeomans, Jae Hyun Kim, Heidi Sucharew, Maurizio Macaluso, Richard M Ruddy, Kathleen A Stringer, Samir S Shah
Background Accurate diagnosis of community-acquired pneumonia (CAP) can be challenging. Clinical findings are non-specific, and interpretations of chest radiographs have poor inter-rater reliability. Pilot studies demonstrate the potential for metabolomics to identify metabolite concentrations that differentiate children with CAP from those without. The objective of this study was to expand these findings in a large cohort of children with CAP compared with controls. Methods Urine was collected from children, 3 months to 12 years old, with emergency department visits for suspected CAP and community-based controls. Nuclear magnetic resonance spectrometry was used to identify and quantify metabolites. A random forest approach developed three models discriminating cases from community-based controls based on: 1) clinical signs and symptoms; 2) metabolites, and 3) the combination of both. The area under the receiver operating characteristic curve (AUC) was computed for each model. Results Included were 253 cases and 122 controls. The metabolite-only model had similar discriminatory ability as the combination model (AUC: 0.97 and 0.99, respectively). The discriminating metabolites in the metabolite-only model were 2-aminobutyrate, fumarate, hypoxanthine, acetone, leucine, quinolinate, valine, O-acetylcarnitine, citrate and trigonelline. In the combined model, discriminatory clinical factors included receipt of corticosteroids, fever, cough, rapid breathing, decreased oral intake, difficulty breathing, receipt of albuterol, abnormal sleepiness, vomiting and wheezing, and included five additional metabolites compared to the metabolite only model (4-hydroxybenzoate, isoleucine, carnitine, 2-hydroxyisovalerate, betaine, succinate). Conclusions Urine metabolite concentrations can accurately discriminate healthy children from children with suspected CAP. Metabolites associated with CAP may overcome limitations of prior diagnostic approaches.
{"title":"Urine Metabolites of Suspected Community-Acquired Pneumonia","authors":"Lilliam Ambroggio, Todd A Florin, Kayla Williamson, Grace Bosma, Brandie D Wagner, Larisa Yeomans, Jae Hyun Kim, Heidi Sucharew, Maurizio Macaluso, Richard M Ruddy, Kathleen A Stringer, Samir S Shah","doi":"10.1093/infdis/jiaf072","DOIUrl":"https://doi.org/10.1093/infdis/jiaf072","url":null,"abstract":"Background Accurate diagnosis of community-acquired pneumonia (CAP) can be challenging. Clinical findings are non-specific, and interpretations of chest radiographs have poor inter-rater reliability. Pilot studies demonstrate the potential for metabolomics to identify metabolite concentrations that differentiate children with CAP from those without. The objective of this study was to expand these findings in a large cohort of children with CAP compared with controls. Methods Urine was collected from children, 3 months to 12 years old, with emergency department visits for suspected CAP and community-based controls. Nuclear magnetic resonance spectrometry was used to identify and quantify metabolites. A random forest approach developed three models discriminating cases from community-based controls based on: 1) clinical signs and symptoms; 2) metabolites, and 3) the combination of both. The area under the receiver operating characteristic curve (AUC) was computed for each model. Results Included were 253 cases and 122 controls. The metabolite-only model had similar discriminatory ability as the combination model (AUC: 0.97 and 0.99, respectively). The discriminating metabolites in the metabolite-only model were 2-aminobutyrate, fumarate, hypoxanthine, acetone, leucine, quinolinate, valine, O-acetylcarnitine, citrate and trigonelline. In the combined model, discriminatory clinical factors included receipt of corticosteroids, fever, cough, rapid breathing, decreased oral intake, difficulty breathing, receipt of albuterol, abnormal sleepiness, vomiting and wheezing, and included five additional metabolites compared to the metabolite only model (4-hydroxybenzoate, isoleucine, carnitine, 2-hydroxyisovalerate, betaine, succinate). Conclusions Urine metabolite concentrations can accurately discriminate healthy children from children with suspected CAP. Metabolites associated with CAP may overcome limitations of prior diagnostic approaches.","PeriodicalId":501010,"journal":{"name":"The Journal of Infectious Diseases","volume":"7 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143401265","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Jennifer A Hughes, Belén P Solans, Anthony J Garcia-Prats, Heather R Draper, H Simon Schaaf, James C Nielsen, Elri Nortier, Ingrid Courtney, Megan Palmer, Louvina van der Laan, Radojka M Savic, Anneke C Hesseling
Background Paediatric pharmacokinetic and safety data for clofazimine are limited. We described the pharmacokinetics and safety of clofazimine in South African children treated for multidrug/rifampicin-resistant tuberculosis (MDR/RR-TB). Methods Children <18 years being routinely treated for MDR/RR-TB were eligible for study participation. Soft gel capsules (Novartis Pharma AG) were administered using WHO-recommended weight-based dosing. Sparse and semi-intensive pharmacokinetic sampling was completed at baseline, Week 2 and 16. Clofazimine weekly area-under-the-concentration-time-curve (wAUC) was compared to target wAUC (60.87 mg*h/L and 111.79 mg*h/L) in adults receiving clofazimine 100mg daily for MDR/RR-TB and leprosy, respectively. Safety monitoring included measurement of QT-interval prolongation and laboratory assessment. Results Twenty children, six (30%) male, median age 6.0 years (range, 1.6-14.4), were included. Median clofazimine wAUC was 162.94 (IQR 130.06–263.95), >25% higher than the target adult wAUC in adults with MDR/RR-TB (111.79; IQR 81.9–151.9). No serious or grade ≥3 cardiac events occurred. There was a linear relationship between clofazimine concentration and QT-interval prolongation with an increase of 0.02 ms for every µg/L. There were 59 adverse events at least possibly related to clofazimine; one severe adverse event (elevated ALT) led to temporary withdrawal of clofazimine. Conclusions Clofazimine doses used achieved substantially higher exposures in children than adults receiving standard clofazimine doses. The association of higher clofazimine exposures and QT-interval prolongation may pose unnecessary risk to children, particularly in combination with other QT-prolonging drugs. Lower clofazimine doses to achieve appropriate clofazimine exposures should be investigated in children using different drug formulations and harmonised weight bands.
{"title":"Pharmacokinetics and safety of clofazimine in children with rifampicin-resistant tuberculosis","authors":"Jennifer A Hughes, Belén P Solans, Anthony J Garcia-Prats, Heather R Draper, H Simon Schaaf, James C Nielsen, Elri Nortier, Ingrid Courtney, Megan Palmer, Louvina van der Laan, Radojka M Savic, Anneke C Hesseling","doi":"10.1093/infdis/jiaf057","DOIUrl":"https://doi.org/10.1093/infdis/jiaf057","url":null,"abstract":"Background Paediatric pharmacokinetic and safety data for clofazimine are limited. We described the pharmacokinetics and safety of clofazimine in South African children treated for multidrug/rifampicin-resistant tuberculosis (MDR/RR-TB). Methods Children &lt;18 years being routinely treated for MDR/RR-TB were eligible for study participation. Soft gel capsules (Novartis Pharma AG) were administered using WHO-recommended weight-based dosing. Sparse and semi-intensive pharmacokinetic sampling was completed at baseline, Week 2 and 16. Clofazimine weekly area-under-the-concentration-time-curve (wAUC) was compared to target wAUC (60.87 mg*h/L and 111.79 mg*h/L) in adults receiving clofazimine 100mg daily for MDR/RR-TB and leprosy, respectively. Safety monitoring included measurement of QT-interval prolongation and laboratory assessment. Results Twenty children, six (30%) male, median age 6.0 years (range, 1.6-14.4), were included. Median clofazimine wAUC was 162.94 (IQR 130.06–263.95), &gt;25% higher than the target adult wAUC in adults with MDR/RR-TB (111.79; IQR 81.9–151.9). No serious or grade ≥3 cardiac events occurred. There was a linear relationship between clofazimine concentration and QT-interval prolongation with an increase of 0.02 ms for every µg/L. There were 59 adverse events at least possibly related to clofazimine; one severe adverse event (elevated ALT) led to temporary withdrawal of clofazimine. Conclusions Clofazimine doses used achieved substantially higher exposures in children than adults receiving standard clofazimine doses. The association of higher clofazimine exposures and QT-interval prolongation may pose unnecessary risk to children, particularly in combination with other QT-prolonging drugs. Lower clofazimine doses to achieve appropriate clofazimine exposures should be investigated in children using different drug formulations and harmonised weight bands.","PeriodicalId":501010,"journal":{"name":"The Journal of Infectious Diseases","volume":"30 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143393458","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Bart G J Dekkers, Huib A M Kerstjens, Helene W Breisnes, Diana J Leeming, Richard M Anthony, Henderik W Frijlink, Tjip S van der Werf, Jos G W Kosterink, Jan-Willem C Alffenaar, Onno W Akkerman
Background Adjunctive host-directed therapies are investigated that modulate host immune responses to reduce excessive inflammation and prevent tissue damage in tuberculosis (TB). Macrolides, including azithromycin, were shown to possess anti-inflammatory and immune-modulatory effects in addition to their antibacterial effects. In the current trial, we investigated whether azithromycin enhances resolution of systemic and pulmonary inflammation and decreases extracellular matrix-related tissue turnover in TB patients. Methods An open label, randomised controlled trial was performed. Adult patients with drug-susceptible, pulmonary TB aged above 18 years were randomly assigned to receive standard anti-TB care or azithromycin 250 mg orally once daily on top of standard care (SoC) for 28 days. Results Twenty-eight patients were included within 4 weeks after initiating anti-TB treatment. Twelve patients in both arms completed the trial. Participants were mostly young, male, had a smoking history and had no co-morbidities. No differences in baseline characteristics were observed between both arms. In blood, azithromycin treatment significantly reduced the TB marker interferon gamma-induced protein-10 (-38% vs -24% vs SoC, P<0.05) and the collagen type IV degradation product C4M (-26% vs -11%, P<0.05). In sputum, treatment with azithromycin significantly reduced neutrophils (-24% vs 0%, P<0.001), neutrophil elastase (-88% vs 75%, P<0.01), and transforming growth factor-β (-86% vs -68%, P<0.05). No significant effects were observed on other parameters. Treatment with azithromycin appeared to be safe. Conclusions The addition of azithromycin to standard anti-TB treatment appears to diminish excess neutrophilic inflammation in patients with pulmonary TB.
{"title":"Azithromycin as host-directed therapy for pulmonary tuberculosis – a randomized pilot trial","authors":"Bart G J Dekkers, Huib A M Kerstjens, Helene W Breisnes, Diana J Leeming, Richard M Anthony, Henderik W Frijlink, Tjip S van der Werf, Jos G W Kosterink, Jan-Willem C Alffenaar, Onno W Akkerman","doi":"10.1093/infdis/jiaf069","DOIUrl":"https://doi.org/10.1093/infdis/jiaf069","url":null,"abstract":"Background Adjunctive host-directed therapies are investigated that modulate host immune responses to reduce excessive inflammation and prevent tissue damage in tuberculosis (TB). Macrolides, including azithromycin, were shown to possess anti-inflammatory and immune-modulatory effects in addition to their antibacterial effects. In the current trial, we investigated whether azithromycin enhances resolution of systemic and pulmonary inflammation and decreases extracellular matrix-related tissue turnover in TB patients. Methods An open label, randomised controlled trial was performed. Adult patients with drug-susceptible, pulmonary TB aged above 18 years were randomly assigned to receive standard anti-TB care or azithromycin 250 mg orally once daily on top of standard care (SoC) for 28 days. Results Twenty-eight patients were included within 4 weeks after initiating anti-TB treatment. Twelve patients in both arms completed the trial. Participants were mostly young, male, had a smoking history and had no co-morbidities. No differences in baseline characteristics were observed between both arms. In blood, azithromycin treatment significantly reduced the TB marker interferon gamma-induced protein-10 (-38% vs -24% vs SoC, P&lt;0.05) and the collagen type IV degradation product C4M (-26% vs -11%, P&lt;0.05). In sputum, treatment with azithromycin significantly reduced neutrophils (-24% vs 0%, P&lt;0.001), neutrophil elastase (-88% vs 75%, P&lt;0.01), and transforming growth factor-β (-86% vs -68%, P&lt;0.05). No significant effects were observed on other parameters. Treatment with azithromycin appeared to be safe. Conclusions The addition of azithromycin to standard anti-TB treatment appears to diminish excess neutrophilic inflammation in patients with pulmonary TB.","PeriodicalId":501010,"journal":{"name":"The Journal of Infectious Diseases","volume":"30 5 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143393913","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Emma Schallenberg, Welmoed van Loon, Djibril Mbarushimana, Clement Igiraneza, Karolina Glanz, Christian Ngarambe, Jules Minega Ndoli, Jason A Hendry, Frank P Mockenhaupt
Background In many countries in Sub-Saharan Africa, the Plasmodium falciparum chloroquine resistance marker pfcrt K76T disappeared within a decade of ceased chloroquine use. Pfaat1 S258L has recently been implicated as another chloroquine resistance marker. Both genes may affect parasite susceptibility to partner drugs in artemisinin-based combination therapy. Rwanda abolished chloroquine in 2001, since 2006 the first-line antimalarial is artemether-lumefantrine. However, partial artemisinin resistance emerged in the region. We assessed the prevalence of pfcrt and pfaat1 markers in Huye district between 2010 -2023, following trends and updating the status in southern Rwanda. Methods P. falciparum positive blood samples from community children and malaria patients collected 2010, 2014, 2018, 2019 and 2023 were examined. Pfcrt K76T was genotyped by RFLP, pfaat1 S258L by high-resolution melting-curve (2010-2019). Samples from 2023 were subjected to nanopore sequencing. Results In 606 samples, pfcrt K76T prevalence declined from 76% (95% confidence interval, 68-83%) to 18% (11-25%) between 2010 and 2018 but stagnated since around 25% (P < 0.001). No further pfcrt markers were observed. Pfaat1 S258L remained at or near fixation. The artemisinin resistance marker pfk13 R561H was associated with pfcrt K76T (P = 0.02). Discussion The persistence of pfcrt K76T 20 years after abolishing chloroquine indicates ongoing drug selection or importation. The fixation of pfaat1 S258L argues against a major fitness cost of this variant in Huye. Partial artemisinin resistance increases in Rwanda, and molecular markers indicate compromised lumefantrine efficacy. The observed pfcrt and pfaat1 signatures in the study area might guide artemisinin partner drug alternatives.
{"title":"Prevalence of Plasmodium falciparum drug resistance markers pfcrt K76T and pfaat1 S258L in southern Rwanda, 2010 to 2023","authors":"Emma Schallenberg, Welmoed van Loon, Djibril Mbarushimana, Clement Igiraneza, Karolina Glanz, Christian Ngarambe, Jules Minega Ndoli, Jason A Hendry, Frank P Mockenhaupt","doi":"10.1093/infdis/jiaf068","DOIUrl":"https://doi.org/10.1093/infdis/jiaf068","url":null,"abstract":"Background In many countries in Sub-Saharan Africa, the Plasmodium falciparum chloroquine resistance marker pfcrt K76T disappeared within a decade of ceased chloroquine use. Pfaat1 S258L has recently been implicated as another chloroquine resistance marker. Both genes may affect parasite susceptibility to partner drugs in artemisinin-based combination therapy. Rwanda abolished chloroquine in 2001, since 2006 the first-line antimalarial is artemether-lumefantrine. However, partial artemisinin resistance emerged in the region. We assessed the prevalence of pfcrt and pfaat1 markers in Huye district between 2010 -2023, following trends and updating the status in southern Rwanda. Methods P. falciparum positive blood samples from community children and malaria patients collected 2010, 2014, 2018, 2019 and 2023 were examined. Pfcrt K76T was genotyped by RFLP, pfaat1 S258L by high-resolution melting-curve (2010-2019). Samples from 2023 were subjected to nanopore sequencing. Results In 606 samples, pfcrt K76T prevalence declined from 76% (95% confidence interval, 68-83%) to 18% (11-25%) between 2010 and 2018 but stagnated since around 25% (P &lt; 0.001). No further pfcrt markers were observed. Pfaat1 S258L remained at or near fixation. The artemisinin resistance marker pfk13 R561H was associated with pfcrt K76T (P = 0.02). Discussion The persistence of pfcrt K76T 20 years after abolishing chloroquine indicates ongoing drug selection or importation. The fixation of pfaat1 S258L argues against a major fitness cost of this variant in Huye. Partial artemisinin resistance increases in Rwanda, and molecular markers indicate compromised lumefantrine efficacy. The observed pfcrt and pfaat1 signatures in the study area might guide artemisinin partner drug alternatives.","PeriodicalId":501010,"journal":{"name":"The Journal of Infectious Diseases","volume":"132 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-02-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143393456","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Sarah S Jackson, Julia Francis, Ruth M Pfeiffer, Carla Proietti, Anna E Coghill, Kelly J Yu, Yomani D Sarathkumara, Wan-Lun Hsu, Ilona Argirion, Cheng-Ping Wang, Chien-Jen Chen, Nathaniel Rothman, Qing Lan, Allan Hildesheim, Denise L Doolan, Zhiwei Liu
We investigated anti-EBV IgA and IgG responses by sex among 387 cancer-free individuals in Asia. Antibody responses were measured using an EBV proteome array to assess age-adjusted sex-specific associations with 404 EBV-antigens in 86 protein sequences via meta-analysis and pathway analysis by EBV stage. Males were more likely to have elevated IgA responses (P=0.001) and females had higher IgG responses (P=0.003). Significant sex associations were observed across stages of lytic replication. The largest sex differences were seen in latent IgA, but no differences were observed in latent IgG antibodies. Higher IgA responses suggest higher rates of EBV reactivation in males.
{"title":"Sex differences in anti-EBV antibody responses","authors":"Sarah S Jackson, Julia Francis, Ruth M Pfeiffer, Carla Proietti, Anna E Coghill, Kelly J Yu, Yomani D Sarathkumara, Wan-Lun Hsu, Ilona Argirion, Cheng-Ping Wang, Chien-Jen Chen, Nathaniel Rothman, Qing Lan, Allan Hildesheim, Denise L Doolan, Zhiwei Liu","doi":"10.1093/infdis/jiaf067","DOIUrl":"https://doi.org/10.1093/infdis/jiaf067","url":null,"abstract":"We investigated anti-EBV IgA and IgG responses by sex among 387 cancer-free individuals in Asia. Antibody responses were measured using an EBV proteome array to assess age-adjusted sex-specific associations with 404 EBV-antigens in 86 protein sequences via meta-analysis and pathway analysis by EBV stage. Males were more likely to have elevated IgA responses (P=0.001) and females had higher IgG responses (P=0.003). Significant sex associations were observed across stages of lytic replication. The largest sex differences were seen in latent IgA, but no differences were observed in latent IgG antibodies. Higher IgA responses suggest higher rates of EBV reactivation in males.","PeriodicalId":501010,"journal":{"name":"The Journal of Infectious Diseases","volume":"57 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-02-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143393459","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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