Stijn van der Veen, Xia Sun, Haoyu Ge, Tran M Chau, Pham Hong Nhung, Koen Vandelannoote, Gauthier Delvallez, Sokleaph Cheng, Jolein Gyonne Elise Laumen, Paul C Adamson
Background: The global dissemination of ceftriaxone-resistant Neisseria gonorrhoeae, primarily associated with mosaic penA alleles, threatens the efficacy of ceftriaxone therapy. While the FC428 clone and its associated penA allele 60.001 are well-documented, data on other emerging resistance-conferring alleles in high-burden regions remain limited. This study characterizes the penA alleles associated with ceftriaxone resistance in Cambodia, China, and Vietnam.
Methods: Publicly available and novel genomes of N. gonorrhoeae isolates from Cambodia, China, and Vietnam with decreased ceftriaxone susceptibility (minimum inhibitory concentration [MIC] ≥ 0.125 mg/L) were analyzed. Multi-locus sequence types and penA alleles were assigned using PubMLST and BIGSdb and a core-genome neighbor-joining phylogenetic tree was constructed. To address selection bias, all isolates with reduced susceptibility from Hangzhou, China (2015-2022), were also analyzed for penA alleles using the NG-STAR method.
Results: Analysis of 236 genomes revealed that ceftriaxone resistance (MIC > 0.125 mg/L) was predominantly associated with penA alleles 60.001 (n = 145) and 237.001 (n = 70), which formed 2 major phylogenetic clades. All resistance-conferring alleles contained the A311 V polymorphism. PenA 60.001 was linked to multiple sequence types (STs), including FC428-associated ST1903 and endemic STs like ST8123 and ST8130. PenA 237.001 was almost exclusively found in Vietnam, primarily in ST1901. Analysis of the unbiased Hangzhou dataset (n = 132) confirmed that high-level resistance (MIC = 0.5-1 mg/L) was exclusively linked to penA 60.001.
Conclusions: Ceftriaxone resistance in the Asia Pacific region is primarily driven by penA 60.001 and 237.001 along with related alleles harboring the A311 V polymorphism. The concerning acquisition of these alleles by successful endemic lineages enhances their potential for local and international spread.
{"title":"PenA Alleles Associated With Gonococcal Ceftriaxone Resistance in Cambodia, China, and Vietnam.","authors":"Stijn van der Veen, Xia Sun, Haoyu Ge, Tran M Chau, Pham Hong Nhung, Koen Vandelannoote, Gauthier Delvallez, Sokleaph Cheng, Jolein Gyonne Elise Laumen, Paul C Adamson","doi":"10.1093/cid/ciaf530","DOIUrl":"10.1093/cid/ciaf530","url":null,"abstract":"<p><strong>Background: </strong>The global dissemination of ceftriaxone-resistant Neisseria gonorrhoeae, primarily associated with mosaic penA alleles, threatens the efficacy of ceftriaxone therapy. While the FC428 clone and its associated penA allele 60.001 are well-documented, data on other emerging resistance-conferring alleles in high-burden regions remain limited. This study characterizes the penA alleles associated with ceftriaxone resistance in Cambodia, China, and Vietnam.</p><p><strong>Methods: </strong>Publicly available and novel genomes of N. gonorrhoeae isolates from Cambodia, China, and Vietnam with decreased ceftriaxone susceptibility (minimum inhibitory concentration [MIC] ≥ 0.125 mg/L) were analyzed. Multi-locus sequence types and penA alleles were assigned using PubMLST and BIGSdb and a core-genome neighbor-joining phylogenetic tree was constructed. To address selection bias, all isolates with reduced susceptibility from Hangzhou, China (2015-2022), were also analyzed for penA alleles using the NG-STAR method.</p><p><strong>Results: </strong>Analysis of 236 genomes revealed that ceftriaxone resistance (MIC > 0.125 mg/L) was predominantly associated with penA alleles 60.001 (n = 145) and 237.001 (n = 70), which formed 2 major phylogenetic clades. All resistance-conferring alleles contained the A311 V polymorphism. PenA 60.001 was linked to multiple sequence types (STs), including FC428-associated ST1903 and endemic STs like ST8123 and ST8130. PenA 237.001 was almost exclusively found in Vietnam, primarily in ST1901. Analysis of the unbiased Hangzhou dataset (n = 132) confirmed that high-level resistance (MIC = 0.5-1 mg/L) was exclusively linked to penA 60.001.</p><p><strong>Conclusions: </strong>Ceftriaxone resistance in the Asia Pacific region is primarily driven by penA 60.001 and 237.001 along with related alleles harboring the A311 V polymorphism. The concerning acquisition of these alleles by successful endemic lineages enhances their potential for local and international spread.</p>","PeriodicalId":10463,"journal":{"name":"Clinical Infectious Diseases","volume":"81 Supplement_5","pages":"S238-S242"},"PeriodicalIF":7.3,"publicationDate":"2026-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12781196/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145932645","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Gail Brenda Cross,Harry N Walker,Tasnim Hasan,Catherine Berry
Bedaquiline has transformed the treatment of multidrug-resistant tuberculosis. However, bedaquiline resistance now threaten these gains. Emerging surveillance data demonstrate both baseline and acquired resistance across high-burden settings, with bedaquiline-resistant disease associated with poor clinical outcomes, high mortality, and growing evidence of transmission. In this Perspective, we examine the converging factors driving this trend, including bedaquiline's unique pharmacokinetic properties and limitations of current drug-susceptibility testing (DST) approaches. We describe critical gaps in phenotypic and genotypic DST, including delayed detection, diagnostic grey zones, and heteroresistance, which undermine timely clinical decision-making. We highlight the need to evaluate bedaquiline-sparing regimens alongside strengthened resistance surveillance, development of composite DST standards, and adoption of rapid molecular tools such as targeted next-generation sequencing. We emphasise the importance of equitable access to effective companion drugs and robust, person-centred treatment support. Coordinated action across clinical, programmatic, and research domains is essential to preserve bedaquiline's efficacy and future TB treatments.
{"title":"We are underprepared for bedaquiline resistance: a call for clinical and programmatic readiness.","authors":"Gail Brenda Cross,Harry N Walker,Tasnim Hasan,Catherine Berry","doi":"10.1093/cid/ciag008","DOIUrl":"https://doi.org/10.1093/cid/ciag008","url":null,"abstract":"Bedaquiline has transformed the treatment of multidrug-resistant tuberculosis. However, bedaquiline resistance now threaten these gains. Emerging surveillance data demonstrate both baseline and acquired resistance across high-burden settings, with bedaquiline-resistant disease associated with poor clinical outcomes, high mortality, and growing evidence of transmission. In this Perspective, we examine the converging factors driving this trend, including bedaquiline's unique pharmacokinetic properties and limitations of current drug-susceptibility testing (DST) approaches. We describe critical gaps in phenotypic and genotypic DST, including delayed detection, diagnostic grey zones, and heteroresistance, which undermine timely clinical decision-making. We highlight the need to evaluate bedaquiline-sparing regimens alongside strengthened resistance surveillance, development of composite DST standards, and adoption of rapid molecular tools such as targeted next-generation sequencing. We emphasise the importance of equitable access to effective companion drugs and robust, person-centred treatment support. Coordinated action across clinical, programmatic, and research domains is essential to preserve bedaquiline's efficacy and future TB treatments.","PeriodicalId":10463,"journal":{"name":"Clinical Infectious Diseases","volume":"23 1","pages":""},"PeriodicalIF":11.8,"publicationDate":"2026-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145907842","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Ayesha Appa, Gabriela Steiner, Stefan Baral, Elise Riley, Lauren Suchman, Kate Roberts, Kelly Knight, Meghan Murphy, Gabriel Chamie, Steve Shoptaw, Phillip O Coffin, Monica Gandhi
Background Stimulants, including cocaine and methamphetamine, are associated with HIV transmission and viremia. Contingency management (CM), which provides financial incentives for non-reactive urine testing, is first-line treatment for stimulant use disorder (StUD), yet has been minimally studied or integrated into HIV care. Methods We conducted a 12-week, single-arm implementation-effectiveness pilot of weekly CM in a safety-net HIV clinic for living with HIV (PWH) who have StUD. Participants received escalating incentives for stimulant-negative and/or tenofovir-reactive point-of-care urine assays. Using the RE-AIM framework, we evaluated Reach (demographics, attendance), Effectiveness (stimulant-negative/tenofovir-positive tests, HIV virologic suppression [VS]), and Implementation. We conducted semi-structured, in-depth participant interviews following intervention completion to explore perceived impact and implementation. Results From September 2023 to February 2024, we enrolled 31 PWH with StUD: 77% used methamphetamine, 35% cocaine, and 19% fentanyl. Only 17/31 (55%) had VS at baseline. Participants attended a mean of 5/12 visits (42%). Among PWH who attended post-enrollment visits (26/31), 61/110 (56%) stimulant tests were negative and 98% (89/91) of tenofovir tests were positive. Post-intervention, 88% (23/26) of retained participants achieved VS (p<0.01). Qualitative interviews revealed factors enhancing Reach (embedding CM within HIV care), Effectiveness (incentives supporting adherence self-efficacy; program providing structure and motivation), and Implementation (supportive staff relationships, non-judgmental approach). Conclusions Contingency management for stimulant use and/or ART adherence (using point-of-care tenofovir assays) embedded into HIV care was associated with reduced stimulant use and gains in viral suppression. Scalability of integrating HIV and stimulant use disorder management using CM merits further evaluation.
{"title":"Integrating HIV and Stimulant Use Disorder Treatment: A Pilot Implementation Effectiveness Trial of Contingency Management in HIV Care","authors":"Ayesha Appa, Gabriela Steiner, Stefan Baral, Elise Riley, Lauren Suchman, Kate Roberts, Kelly Knight, Meghan Murphy, Gabriel Chamie, Steve Shoptaw, Phillip O Coffin, Monica Gandhi","doi":"10.1093/cid/ciag006","DOIUrl":"https://doi.org/10.1093/cid/ciag006","url":null,"abstract":"Background Stimulants, including cocaine and methamphetamine, are associated with HIV transmission and viremia. Contingency management (CM), which provides financial incentives for non-reactive urine testing, is first-line treatment for stimulant use disorder (StUD), yet has been minimally studied or integrated into HIV care. Methods We conducted a 12-week, single-arm implementation-effectiveness pilot of weekly CM in a safety-net HIV clinic for living with HIV (PWH) who have StUD. Participants received escalating incentives for stimulant-negative and/or tenofovir-reactive point-of-care urine assays. Using the RE-AIM framework, we evaluated Reach (demographics, attendance), Effectiveness (stimulant-negative/tenofovir-positive tests, HIV virologic suppression [VS]), and Implementation. We conducted semi-structured, in-depth participant interviews following intervention completion to explore perceived impact and implementation. Results From September 2023 to February 2024, we enrolled 31 PWH with StUD: 77% used methamphetamine, 35% cocaine, and 19% fentanyl. Only 17/31 (55%) had VS at baseline. Participants attended a mean of 5/12 visits (42%). Among PWH who attended post-enrollment visits (26/31), 61/110 (56%) stimulant tests were negative and 98% (89/91) of tenofovir tests were positive. Post-intervention, 88% (23/26) of retained participants achieved VS (p&lt;0.01). Qualitative interviews revealed factors enhancing Reach (embedding CM within HIV care), Effectiveness (incentives supporting adherence self-efficacy; program providing structure and motivation), and Implementation (supportive staff relationships, non-judgmental approach). Conclusions Contingency management for stimulant use and/or ART adherence (using point-of-care tenofovir assays) embedded into HIV care was associated with reduced stimulant use and gains in viral suppression. Scalability of integrating HIV and stimulant use disorder management using CM merits further evaluation.","PeriodicalId":10463,"journal":{"name":"Clinical Infectious Diseases","volume":"227 1","pages":""},"PeriodicalIF":11.8,"publicationDate":"2026-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145920333","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Nguyen Thi Mai Thu,Lottie Brown,Oriana Hawkins,Konner Bloss,Sruthi Venugopalan,Meredith Brown,Jonathan Fenhaus,Heera Natesan Sambath,Jialin Liu,Lyla Clancy,Jian-Piao Cai,Jasper Fuk-Woo Chan,K Y Yuen,Vo Trieu Ly,Ngo Thi Hoa,Thuy Le
BACKGROUNDThe diagnosis of talaromycosis, a life-threatening invasive fungal disease endemic in Southeast Asia, still relies on protracted culture methods. We report the development and clinical evaluation of a novel lateral flow assay (LFA) for the rapid diagnosis of talaromycosis.METHODSThe LFA used two novel monoclonal antibodies targeting the Talaromyces marneffei-specific protein Mp1p. In a retrospective, case-cohort study, we evaluated the diagnostic performance of the Mp1p LFA against the reference standard of culture-proven talaromycosis from any clinical specimens, and compared to our validated Mp1p enzyme immunoassay (EIA) in paired plasma and urine samples from 239 talaromycosis and 160 non-talaromycosis participants randomly selected from cohorts of hospitalized adults with advanced HIV disease from five centers across Vietnam.RESULTSThe Mp1p LFA demonstrated an analytical limit-of-detection of 400 pg/mL, comparable to the EIA. No cross-reactivity with 16 common human fungal pathogens was observed. Clinical sensitivity was higher in urine compared to plasma (95.4% vs 88.7%, P < 0.01), and clinical specificity was >95% in both specimen types. Clinical performance was similar to the EIA: sensitivity 95.4% vs 97.1%, P = 0.87 and specificity 95.6% vs 97.5%, P = 1.0. Both the LFA and EIA were substantially more sensitive than conventional blood culture collected at the same time (95.4% vs 97.1% vs 77.8%, P < 0.01).CONCLUSIONThe Mp1p LFA has excellent diagnostic performance, comparable to the EIA, is superior to blood culture, and has the potential to rapidly rule-in and rule-out talaromycosis at the point-of-care within 15 minutes without need for laboratory infrastructure.
背景：东南亚流行的一种危及生命的侵袭性真菌病，其诊断仍然依赖于长期培养方法。我们报告的发展和临床评估一种新的横向流动试验（LFA）的快速诊断塔兰菌病。方法LFA采用两种新型单克隆抗体靶向Talaromyces marneffei特异性蛋白Mp1p。在一项回顾性的病例队列研究中，我们评估了Mp1p LFA对任何临床标本中培养证实的塔拉芳香菌病的参考标准的诊断性能，并与我们在配对血浆和尿液样本中验证的Mp1p酶免疫测定（EIA）进行了比较，这些样本来自越南五个中心随机选择的239名塔拉芳香菌病和160名非塔拉芳香菌病参与者。结果Mp1p LFA的分析检出限为400 pg/mL，与EIA相当。与16种常见的人类真菌病原体无交叉反应。尿液的临床敏感性高于血浆（95.4% vs 88.7%, P < 0.01），两种标本类型的临床特异性均为0.95%。临床表现与EIA相似：敏感性95.4% vs 97.1%, P = 0.87；特异性95.6% vs 97.5%, P = 1.0。LFA和EIA的敏感性均显著高于同时采集的常规血培养（95.4% vs 97.1% vs 77.8%, P < 0.01）。结论Mp1p LFA具有优异的诊断性能，可与EIA相媲美，优于血培养，具有在15分钟内快速诊断和排除talaromyosis的潜力，无需实验室基础设施。
{"title":"Development and Clinical Evaluation of a Novel Talaromyces marneffei Mp1p Lateral Flow Assay for Rapid Diagnosis of Talaromycosis.","authors":"Nguyen Thi Mai Thu,Lottie Brown,Oriana Hawkins,Konner Bloss,Sruthi Venugopalan,Meredith Brown,Jonathan Fenhaus,Heera Natesan Sambath,Jialin Liu,Lyla Clancy,Jian-Piao Cai,Jasper Fuk-Woo Chan,K Y Yuen,Vo Trieu Ly,Ngo Thi Hoa,Thuy Le","doi":"10.1093/cid/ciag004","DOIUrl":"https://doi.org/10.1093/cid/ciag004","url":null,"abstract":"BACKGROUNDThe diagnosis of talaromycosis, a life-threatening invasive fungal disease endemic in Southeast Asia, still relies on protracted culture methods. We report the development and clinical evaluation of a novel lateral flow assay (LFA) for the rapid diagnosis of talaromycosis.METHODSThe LFA used two novel monoclonal antibodies targeting the Talaromyces marneffei-specific protein Mp1p. In a retrospective, case-cohort study, we evaluated the diagnostic performance of the Mp1p LFA against the reference standard of culture-proven talaromycosis from any clinical specimens, and compared to our validated Mp1p enzyme immunoassay (EIA) in paired plasma and urine samples from 239 talaromycosis and 160 non-talaromycosis participants randomly selected from cohorts of hospitalized adults with advanced HIV disease from five centers across Vietnam.RESULTSThe Mp1p LFA demonstrated an analytical limit-of-detection of 400 pg/mL, comparable to the EIA. No cross-reactivity with 16 common human fungal pathogens was observed. Clinical sensitivity was higher in urine compared to plasma (95.4% vs 88.7%, P < 0.01), and clinical specificity was >95% in both specimen types. Clinical performance was similar to the EIA: sensitivity 95.4% vs 97.1%, P = 0.87 and specificity 95.6% vs 97.5%, P = 1.0. Both the LFA and EIA were substantially more sensitive than conventional blood culture collected at the same time (95.4% vs 97.1% vs 77.8%, P < 0.01).CONCLUSIONThe Mp1p LFA has excellent diagnostic performance, comparable to the EIA, is superior to blood culture, and has the potential to rapidly rule-in and rule-out talaromycosis at the point-of-care within 15 minutes without need for laboratory infrastructure.","PeriodicalId":10463,"journal":{"name":"Clinical Infectious Diseases","volume":"28 1","pages":""},"PeriodicalIF":11.8,"publicationDate":"2026-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145907699","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Amanda J Sheets,Jeremy Dennison,Jason M Pogue,Keith S Kaye,Caroline Perry,Helen Millns,Jazmín Díaz-Regañón,Salim Janmohamed
BACKGROUNDUncomplicated urinary tract infections (uUTIs) can cause distressing symptoms seriously impacting daily activities. Early symptom relief during treatment, though fundamental to patients, is often overlooked in clinical trials. Gepotidacin, a new antibacterial agent, was noninferior to the first-line treatment nitrofurantoin in two randomized controlled trials (EAGLE-2 [NCT04020341] and EAGLE-3 [NCT04187144]). The current analysis utilized pooled data from these two trials to evaluate symptom responses during and after treatment in participants with uUTI.METHODSParticipants were aged ≥12 years with at least two uUTI symptoms, urinary nitrite and/or pyuria, and no complicating factors. Participants were randomized 1:1 to oral gepotidacin (1500 mg) or nitrofurantoin (100 mg), both taken twice daily for 5 days. At baseline (Day 1), on-therapy (OT; Day 2-4), and test-of-cure (TOC; Day 10-13) visits, urinary symptoms were assessed (0-3; none-severe) from which a total score (0-12) was derived.RESULTSOverall, 3136 participants were randomized (1572 gepotidacin, 1564 nitrofurantoin). Mean (median) baseline symptom scores for gepotidacin and nitrofurantoin arms were 7.1 (7.0) and 7.2 (7.0), respectively; at OT, this decreased to 3.6 (3.0) for both arms. At the OT visit, >80% of participants had clinical improvement/resolution. Among those with baseline symptoms affecting everyday activities (moderate or severe), 53.2% (728/1369) assigned gepotidacin and 53.6% (738/1377) assigned nitrofurantoin reported at OT that symptoms no longer affected everyday activities (mild or absent); at TOC, these percentages were 93.8% (1232/1313) and 93.3% (1254/1344), respectively.CONCLUSIONSGepotidacin and nitrofurantoin provide meaningful and similar early relief from uUTI symptoms.
{"title":"Early symptom response in patients with uncomplicated urinary tract infection treated with gepotidacin or nitrofurantoin: pooled analysis from two pivotal Phase 3 studies.","authors":"Amanda J Sheets,Jeremy Dennison,Jason M Pogue,Keith S Kaye,Caroline Perry,Helen Millns,Jazmín Díaz-Regañón,Salim Janmohamed","doi":"10.1093/cid/ciaf722","DOIUrl":"https://doi.org/10.1093/cid/ciaf722","url":null,"abstract":"BACKGROUNDUncomplicated urinary tract infections (uUTIs) can cause distressing symptoms seriously impacting daily activities. Early symptom relief during treatment, though fundamental to patients, is often overlooked in clinical trials. Gepotidacin, a new antibacterial agent, was noninferior to the first-line treatment nitrofurantoin in two randomized controlled trials (EAGLE-2 [NCT04020341] and EAGLE-3 [NCT04187144]). The current analysis utilized pooled data from these two trials to evaluate symptom responses during and after treatment in participants with uUTI.METHODSParticipants were aged ≥12 years with at least two uUTI symptoms, urinary nitrite and/or pyuria, and no complicating factors. Participants were randomized 1:1 to oral gepotidacin (1500 mg) or nitrofurantoin (100 mg), both taken twice daily for 5 days. At baseline (Day 1), on-therapy (OT; Day 2-4), and test-of-cure (TOC; Day 10-13) visits, urinary symptoms were assessed (0-3; none-severe) from which a total score (0-12) was derived.RESULTSOverall, 3136 participants were randomized (1572 gepotidacin, 1564 nitrofurantoin). Mean (median) baseline symptom scores for gepotidacin and nitrofurantoin arms were 7.1 (7.0) and 7.2 (7.0), respectively; at OT, this decreased to 3.6 (3.0) for both arms. At the OT visit, >80% of participants had clinical improvement/resolution. Among those with baseline symptoms affecting everyday activities (moderate or severe), 53.2% (728/1369) assigned gepotidacin and 53.6% (738/1377) assigned nitrofurantoin reported at OT that symptoms no longer affected everyday activities (mild or absent); at TOC, these percentages were 93.8% (1232/1313) and 93.3% (1254/1344), respectively.CONCLUSIONSGepotidacin and nitrofurantoin provide meaningful and similar early relief from uUTI symptoms.","PeriodicalId":10463,"journal":{"name":"Clinical Infectious Diseases","volume":"21 1","pages":""},"PeriodicalIF":11.8,"publicationDate":"2026-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145907846","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Biyue Dai,Nicole Engen,Caleb P Skipper,Mahsa Abassi,Laura Nsangi,Thomas C McHale,David B Meya,David R Boulware
BACKGROUNDTraditional antifungal trials have relied on all-cause mortality as the primary endpoint, which may overlook important treatment-related outcomes such as adverse events or tolerability.METHODSWe evaluated the use of hierarchical composite endpoints to capture clinically meaningful treatment differences in cryptococcal meningitis trials. A Delphi survey determined priorities in constructing the composite endpoint. We analyzed three randomized clinical trials on cryptococcal meningitis with Win Ratio and the Desirability of Outcome Ranking (DOOR). We estimated the Better DOOR Probability (BDP), which is the probability that a participant assigned to the study treatment would have a more desirable outcome.RESULTSThe Delphi survey received 34 respondents and most of them prioritized mortality and serious adverse events. In the AMBITION-cm trial, single-dose liposomal amphotericin B yielded a BDP of 55% (95%CI, 51-59%) and Win Ratio of 1.23 (95%CI, 1.03-1.46), indicating superiority over standard-of-care therapy. In ENACT phase II trial, oral amphotericin B was associated with BDP of 52% (95%CI, 42-63%) and Win Ratio of 1.14 (95%CI, 0.68-1.91), showing no statistically significant difference. The ASTRO-CM trial testing adjunctive sertraline showed no overall benefit with sertraline using either BDP (46%; 95%CI, 41-52%) or Win Ratio 0.87 (95%CI, 0.70-1.08).CONCLUSIONSHierarchical composite endpoints were feasible to implement in cryptococcal meningitis clinical trials and can enhance clinical relevance, especially in non-inferiority designs where safety and tolerability matter. The two statistical approaches provided complementary perspectives - DOOR offering absolute ranks and Win Ratio providing a more interpretable relative treatment effect estimate.
{"title":"Evaluating Desirability of Outcome Ranking (DOOR) and Win Ratio for Hierarchical Composite Endpoints in Cryptococcal Meningitis Trials.","authors":"Biyue Dai,Nicole Engen,Caleb P Skipper,Mahsa Abassi,Laura Nsangi,Thomas C McHale,David B Meya,David R Boulware","doi":"10.1093/cid/ciaf719","DOIUrl":"https://doi.org/10.1093/cid/ciaf719","url":null,"abstract":"BACKGROUNDTraditional antifungal trials have relied on all-cause mortality as the primary endpoint, which may overlook important treatment-related outcomes such as adverse events or tolerability.METHODSWe evaluated the use of hierarchical composite endpoints to capture clinically meaningful treatment differences in cryptococcal meningitis trials. A Delphi survey determined priorities in constructing the composite endpoint. We analyzed three randomized clinical trials on cryptococcal meningitis with Win Ratio and the Desirability of Outcome Ranking (DOOR). We estimated the Better DOOR Probability (BDP), which is the probability that a participant assigned to the study treatment would have a more desirable outcome.RESULTSThe Delphi survey received 34 respondents and most of them prioritized mortality and serious adverse events. In the AMBITION-cm trial, single-dose liposomal amphotericin B yielded a BDP of 55% (95%CI, 51-59%) and Win Ratio of 1.23 (95%CI, 1.03-1.46), indicating superiority over standard-of-care therapy. In ENACT phase II trial, oral amphotericin B was associated with BDP of 52% (95%CI, 42-63%) and Win Ratio of 1.14 (95%CI, 0.68-1.91), showing no statistically significant difference. The ASTRO-CM trial testing adjunctive sertraline showed no overall benefit with sertraline using either BDP (46%; 95%CI, 41-52%) or Win Ratio 0.87 (95%CI, 0.70-1.08).CONCLUSIONSHierarchical composite endpoints were feasible to implement in cryptococcal meningitis clinical trials and can enhance clinical relevance, especially in non-inferiority designs where safety and tolerability matter. The two statistical approaches provided complementary perspectives - DOOR offering absolute ranks and Win Ratio providing a more interpretable relative treatment effect estimate.","PeriodicalId":10463,"journal":{"name":"Clinical Infectious Diseases","volume":"29 1","pages":""},"PeriodicalIF":11.8,"publicationDate":"2026-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145907845","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Ava Hunt, Elena Martin, Blake Gilberto-Bono, Joseph Ladines-Lim, Anne Norris, Christina O’Malley, Bhavana Kunisetty, Sara Clemens
Access to Infectious Disease (ID) specialists is limited. We analyzed 515 ID electronic provider-to-provider consultations (eConsults) over a 10-month period, finding high utilization for immunocompromised patients. Most eConsults were billable, averaging $190.65/hour. Referring providers reported high satisfaction. eConsults are one financially viable way to improve access to ID specialty care.
{"title":"Assessment of an Infectious Disease eConsult Service at a Large Mid-Atlantic Healthcare System","authors":"Ava Hunt, Elena Martin, Blake Gilberto-Bono, Joseph Ladines-Lim, Anne Norris, Christina O’Malley, Bhavana Kunisetty, Sara Clemens","doi":"10.1093/cid/ciaf736","DOIUrl":"https://doi.org/10.1093/cid/ciaf736","url":null,"abstract":"Access to Infectious Disease (ID) specialists is limited. We analyzed 515 ID electronic provider-to-provider consultations (eConsults) over a 10-month period, finding high utilization for immunocompromised patients. Most eConsults were billable, averaging $190.65/hour. Referring providers reported high satisfaction. eConsults are one financially viable way to improve access to ID specialty care.","PeriodicalId":10463,"journal":{"name":"Clinical Infectious Diseases","volume":"125 1","pages":""},"PeriodicalIF":11.8,"publicationDate":"2026-01-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145903699","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Billal Musah Obeng, Jolie Hutchinson, Ansari Shaik, Ploenchan Chetchotisakd, Iskandar Azwa, Wahyu Nawang Wulan, Nagalingeswaran Kumarasamy, Marcelo Wolff, José Bruguera, Marcelo Losso, Richard Kaplan, Mariama Sadjo Diallo, Nnakelu Eriobu, Godfrey Musoro, July Kumalawati, Abba Badamasi, Munawaroh Fitriah, Deshinta Putri Mulya, Matthew Law, Gail Matthews, Francesca Di Giallonardo, Anthony Dominic Kelleher
Introduction: D²EFT (Dolutegravir and Darunavir Evaluation in Adults Failing Therapy) was a phase 3b/4 randomized clinical trial designed to assess second-line treatment options systematically. This sub-study evaluated the distribution of drug resistance mutations (DRMs) before treatment randomisation in individuals failing first-line therapy.
Methods: From a total of 826 participants across 14 countries, 727 sequences that covered the pr-rt-int (700), pr-rt (24), and rt (3) were analyzed for drug resistance. Sequences were submitted to the Stanford HIV drug resistance database to detect DRMs and assign subtypes. By adjusting for country and ART regimen, we assessed the association between DRMs and country and reported DRMs.
Results: Subtype C of HIV-1 accounted for most (59.3%) infections. There were extraordinarily high rates of high-level resistance to 3TC and FTC, both at 88.3%, and for EFV and NVP, at 92.8% and 96.8%, respectively. On average, nucleoside reverse transcriptase inhibitors (NRTI) mutations had the highest occurrence across countries with M184V/I detected in 86.2% of the samples, while the highest proportion of non-nucleoside reverse transcriptase inhibitors (NNRTI) mutations was K103N at 57.8%. K103N had an increased likelihood of occurrence in African and South American countries (p<0.05). Participants with prior exposure to a ZDV-containing regimen had an increased likelihood of T215F/Y mutations 6.80[2.59, 17.86], while those with NVP/RPV exposure had a decreased likelihood of K103N mutation 0.29[0.15, 0.56].
Conclusion: The regional specificity of mutations underscores the dynamic nature of HIV-1 drug resistance patterns and the importance of monitoring and understanding local mutation profiles.
{"title":"Regional variations of rates and determinants of drug resistance mutations in people failing first-line therapy for HIV-1: a substudy from the D2EFT phase 3b/4 clinical trial.","authors":"Billal Musah Obeng, Jolie Hutchinson, Ansari Shaik, Ploenchan Chetchotisakd, Iskandar Azwa, Wahyu Nawang Wulan, Nagalingeswaran Kumarasamy, Marcelo Wolff, José Bruguera, Marcelo Losso, Richard Kaplan, Mariama Sadjo Diallo, Nnakelu Eriobu, Godfrey Musoro, July Kumalawati, Abba Badamasi, Munawaroh Fitriah, Deshinta Putri Mulya, Matthew Law, Gail Matthews, Francesca Di Giallonardo, Anthony Dominic Kelleher","doi":"10.1093/cid/ciaf739","DOIUrl":"https://doi.org/10.1093/cid/ciaf739","url":null,"abstract":"<p><strong>Introduction: </strong>D²EFT (Dolutegravir and Darunavir Evaluation in Adults Failing Therapy) was a phase 3b/4 randomized clinical trial designed to assess second-line treatment options systematically. This sub-study evaluated the distribution of drug resistance mutations (DRMs) before treatment randomisation in individuals failing first-line therapy.</p><p><strong>Methods: </strong>From a total of 826 participants across 14 countries, 727 sequences that covered the pr-rt-int (700), pr-rt (24), and rt (3) were analyzed for drug resistance. Sequences were submitted to the Stanford HIV drug resistance database to detect DRMs and assign subtypes. By adjusting for country and ART regimen, we assessed the association between DRMs and country and reported DRMs.</p><p><strong>Results: </strong>Subtype C of HIV-1 accounted for most (59.3%) infections. There were extraordinarily high rates of high-level resistance to 3TC and FTC, both at 88.3%, and for EFV and NVP, at 92.8% and 96.8%, respectively. On average, nucleoside reverse transcriptase inhibitors (NRTI) mutations had the highest occurrence across countries with M184V/I detected in 86.2% of the samples, while the highest proportion of non-nucleoside reverse transcriptase inhibitors (NNRTI) mutations was K103N at 57.8%. K103N had an increased likelihood of occurrence in African and South American countries (p<0.05). Participants with prior exposure to a ZDV-containing regimen had an increased likelihood of T215F/Y mutations 6.80[2.59, 17.86], while those with NVP/RPV exposure had a decreased likelihood of K103N mutation 0.29[0.15, 0.56].</p><p><strong>Conclusion: </strong>The regional specificity of mutations underscores the dynamic nature of HIV-1 drug resistance patterns and the importance of monitoring and understanding local mutation profiles.</p>","PeriodicalId":10463,"journal":{"name":"Clinical Infectious Diseases","volume":" ","pages":""},"PeriodicalIF":7.3,"publicationDate":"2026-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145892282","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Background The causal relationship between Crohn’s disease (CD) and Mycobacterium avium subspecies paratuberculosis (MAP) remains controversial. Methods This multicenter observational study was conducted across seven tertiary care centers in India enrolled newly diagnosed, treatment-naïve Crohn’s disease (CD) patients as cases, and treatment-naïve intestinal tuberculosis (ITB), ulcerative colitis (UC), and healthy individuals undergoing sigmoidoscopy for hemorrhoids as controls. Mycobacterium avium subspecies paratuberculosis (MAP) detection was performed using serology for MAP antibodies, PCR, RT-qPCR, and solid/liquid cultures on blood and colonic biopsies. In situ PCR and immunohistochemistry (IHC) were additionally applied to paraffin-embedded tissue sections to evaluate MAP presence across groups. Findings A total of 889 participants were recruited (CD=148, ITB=288, UC=251 and non-IBD controls=202) were included. The seropositivity of MAP was significantly higher in patients with CD compared to controls (20.6% [13/63] vs healthy controls: 16.2% [12/74]; ITB: 7.8% [9/116]; UC: 4.8% [4/84]; p<0.01). On tissue PCR analysis using IS900-specific sequence in colonic biopsies, statistically higher number of patients with CD were positive for MAP compared to controls (11% [9/82] vs 7.1% [5/70]; UC: 1% [2/188]; ITB: 0.5% [1/198]; p<0.01). On solid culture of biopsy samples, MAP was detected in 10% (5/50) of patients with CD compared to 4.1% (4/97) in ITB and 0% (0/78) in UC (p=0.02). However, this difference was not observed when analysed using liquid culture, IHC, in situ PCR, and PCR of blood samples. Interpretation Findings of our study suggest an increased association of MAP and CD. Future studies should explore possible causal role of MAP in CD and potential therapeutic options to target MAP.
{"title":"Association of Mycobacterium Avium paratuberculosis with Crohn’s Disease: A large multicentre study from TB endemic region","authors":"Sudheer Kumar Vuyyuru, Urvashi Singh, Prasenjit Das, Shiv Basant, Vishwajeet Singh, Saroj Kant Sinha, Kusum Sharma, B S Ramakrishnan, P Kannan, Rupesh Pokharna, Bharti Malhotra, Shobna Bhatia, Gopal Krishna Dhali, Rajib Sarkar, Charu Sharma, Siddhartha Dattagupta, Manjula Singh, Rakesh Kochhar, Sreenivas Vishnubhatla, Vineet Ahuja","doi":"10.1093/cid/ciaf738","DOIUrl":"https://doi.org/10.1093/cid/ciaf738","url":null,"abstract":"Background The causal relationship between Crohn’s disease (CD) and Mycobacterium avium subspecies paratuberculosis (MAP) remains controversial. Methods This multicenter observational study was conducted across seven tertiary care centers in India enrolled newly diagnosed, treatment-naïve Crohn’s disease (CD) patients as cases, and treatment-naïve intestinal tuberculosis (ITB), ulcerative colitis (UC), and healthy individuals undergoing sigmoidoscopy for hemorrhoids as controls. Mycobacterium avium subspecies paratuberculosis (MAP) detection was performed using serology for MAP antibodies, PCR, RT-qPCR, and solid/liquid cultures on blood and colonic biopsies. In situ PCR and immunohistochemistry (IHC) were additionally applied to paraffin-embedded tissue sections to evaluate MAP presence across groups. Findings A total of 889 participants were recruited (CD=148, ITB=288, UC=251 and non-IBD controls=202) were included. The seropositivity of MAP was significantly higher in patients with CD compared to controls (20.6% [13/63] vs healthy controls: 16.2% [12/74]; ITB: 7.8% [9/116]; UC: 4.8% [4/84]; p&lt;0.01). On tissue PCR analysis using IS900-specific sequence in colonic biopsies, statistically higher number of patients with CD were positive for MAP compared to controls (11% [9/82] vs 7.1% [5/70]; UC: 1% [2/188]; ITB: 0.5% [1/198]; p&lt;0.01). On solid culture of biopsy samples, MAP was detected in 10% (5/50) of patients with CD compared to 4.1% (4/97) in ITB and 0% (0/78) in UC (p=0.02). However, this difference was not observed when analysed using liquid culture, IHC, in situ PCR, and PCR of blood samples. Interpretation Findings of our study suggest an increased association of MAP and CD. Future studies should explore possible causal role of MAP in CD and potential therapeutic options to target MAP.","PeriodicalId":10463,"journal":{"name":"Clinical Infectious Diseases","volume":"1 1","pages":""},"PeriodicalIF":11.8,"publicationDate":"2026-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145897428","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Introduction Although anal cancer is rare, it disproportionately affects high-risk groups such as men who have sex with men (MSM) and people with HIV. MSM using Pre-Exposure Prophylaxis (MSM-PrEP) represent an emerging subgroup with behavioral risk factors that may increase susceptibility to high-risk human papillomavirus (HR HPV) infection and anal high-grade squamous intraepithelial lesions (HSIL). However, data on precancerous anal lesions in this group remain unexplored. Objective To compare the prevalence and distribution of histological abnormalities detected via high-resolution anoscopy (HRA) between MSM-PrEP and MSM with HIV (HIV+MSM) and to explore the association between anal HSIL and anal swab results using cytology and HR HPV testing. Methods This secondary exploratory analysis extended a prospective, monocentric cross-sectional study on cytology and HPV infection conducted at the HIV Reference Centre and PrEP Clinic of Universitair Ziekenhuis Brussel by incorporating histological data. Results A total of 85 MSM-PrEP and 93 HIV+MSM underwent HRA. Histologically confirmed anal HSIL did not differ significantly between MSM-PrEP and HIV+MSM (OR 0.6, 95% CI 0.32–1.25). No significant variation was observed in the overall histological outcome distribution (p = 0.401). A history of gonorrhea was significantly associated with HSIL (OR 2.39, 95% CI 1.03–5.55). Cytology showed limited discriminatory value, while HR HPV infection was present in all HSIL cases. Many lesions were linked to HR HPV types other than HPV16. Conclusions MSM-PrEP may be at similarly high risk for anal HSIL as HIV+ MSM, underscoring the need for tailored screening strategies.
{"title":"HPV-Related Anal Precancerous Lesions in MSM: A Comparative Study of PrEP Users and HIV-Positive Individuals","authors":"Magali Surmont, Michel Verheyden, Shaira Sahebali, Mathijs Goossens, Sabine Allard, Sebastien Kindt","doi":"10.1093/cid/ciaf724","DOIUrl":"https://doi.org/10.1093/cid/ciaf724","url":null,"abstract":"Introduction Although anal cancer is rare, it disproportionately affects high-risk groups such as men who have sex with men (MSM) and people with HIV. MSM using Pre-Exposure Prophylaxis (MSM-PrEP) represent an emerging subgroup with behavioral risk factors that may increase susceptibility to high-risk human papillomavirus (HR HPV) infection and anal high-grade squamous intraepithelial lesions (HSIL). However, data on precancerous anal lesions in this group remain unexplored. Objective To compare the prevalence and distribution of histological abnormalities detected via high-resolution anoscopy (HRA) between MSM-PrEP and MSM with HIV (HIV+MSM) and to explore the association between anal HSIL and anal swab results using cytology and HR HPV testing. Methods This secondary exploratory analysis extended a prospective, monocentric cross-sectional study on cytology and HPV infection conducted at the HIV Reference Centre and PrEP Clinic of Universitair Ziekenhuis Brussel by incorporating histological data. Results A total of 85 MSM-PrEP and 93 HIV+MSM underwent HRA. Histologically confirmed anal HSIL did not differ significantly between MSM-PrEP and HIV+MSM (OR 0.6, 95% CI 0.32–1.25). No significant variation was observed in the overall histological outcome distribution (p = 0.401). A history of gonorrhea was significantly associated with HSIL (OR 2.39, 95% CI 1.03–5.55). Cytology showed limited discriminatory value, while HR HPV infection was present in all HSIL cases. Many lesions were linked to HR HPV types other than HPV16. Conclusions MSM-PrEP may be at similarly high risk for anal HSIL as HIV+ MSM, underscoring the need for tailored screening strategies.","PeriodicalId":10463,"journal":{"name":"Clinical Infectious Diseases","volume":"22 1","pages":""},"PeriodicalIF":11.8,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145897427","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
扫码关注我们
求助内容：
应助结果提醒方式：
京公网安备 11010802042870号