Jessica Barrett, Ernest Muntengesa, Clare Warrell, Tommy Rampling, Jodie Owen, Dipti Patel, Sanjay Bhagani, Rachel Moores, Antonia Scobie
Objectives: Yellow fever-associated viscerotropic disease (YEL-AVD) is a rare but serious complication arising from administration of live-attenuated yellow fever vaccine to individuals with risk factors such as thymectomy. At present there is no evidence-based treatment, and case fatality rates are high. Sofosbuvir, an NS5B nucleotide inhibitor, has activity against yellow fever virus in vitro and in vivo.
Patient and methods: Here we describe clinical and virological response to use of off-licence sofosbuvir as post-exposure prophylaxis for a patient inadvertently given yellow fever vaccine despite previous thymectomy.
Results: A 14-day course of oral sofosbuvir was administered in an outpatient setting with regular clinical and biochemical monitoring. The patient remained well without developing clinical features of YEL-AVD and did not experience adverse effects from the treatment.
Conclusions: This supports the use of sofosbuvir as post-exposure prophylaxis in patients at high risk of developing YEL-AVD. Ongoing trials of efficacy of sofosbuvir in yellow fever infection may result in stronger support for this approach in the future.
{"title":"Sofosbuvir as post-exposure prophylaxis for yellow fever-associated viscerotropic disease (YEL-AVD).","authors":"Jessica Barrett, Ernest Muntengesa, Clare Warrell, Tommy Rampling, Jodie Owen, Dipti Patel, Sanjay Bhagani, Rachel Moores, Antonia Scobie","doi":"10.1093/jac/dkae484","DOIUrl":"10.1093/jac/dkae484","url":null,"abstract":"<p><strong>Objectives: </strong>Yellow fever-associated viscerotropic disease (YEL-AVD) is a rare but serious complication arising from administration of live-attenuated yellow fever vaccine to individuals with risk factors such as thymectomy. At present there is no evidence-based treatment, and case fatality rates are high. Sofosbuvir, an NS5B nucleotide inhibitor, has activity against yellow fever virus in vitro and in vivo.</p><p><strong>Patient and methods: </strong>Here we describe clinical and virological response to use of off-licence sofosbuvir as post-exposure prophylaxis for a patient inadvertently given yellow fever vaccine despite previous thymectomy.</p><p><strong>Results: </strong>A 14-day course of oral sofosbuvir was administered in an outpatient setting with regular clinical and biochemical monitoring. The patient remained well without developing clinical features of YEL-AVD and did not experience adverse effects from the treatment.</p><p><strong>Conclusions: </strong>This supports the use of sofosbuvir as post-exposure prophylaxis in patients at high risk of developing YEL-AVD. Ongoing trials of efficacy of sofosbuvir in yellow fever infection may result in stronger support for this approach in the future.</p>","PeriodicalId":14969,"journal":{"name":"Journal of Antimicrobial Chemotherapy","volume":" ","pages":"825-827"},"PeriodicalIF":3.9,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143005910","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Inés Suárez-García, Belén Alejos, Cristina Moreno, Juan Martín Torres, Mar Masiá, Lucio J García-Fraile, Melchor Riera, David Dalmau, Rafael Rodríguez-Rosado, Roberto Muga, Santiago Moreno, Inma Jarrín
Objectives: To evaluate the long-term effectiveness, persistence and tolerability of dolutegravir (DTG)/lamivudine (3TC), compared with the most frequently prescribed first-line treatment regimens, among antiretroviral-naive people with HIV from CoRIS, a multicentre cohort in Spain, in 2018-23.
Methods: We used multivariable regression models to compare viral suppression (VS) (HIV RNA viral load <50 copies/mL), change in CD4 cell counts, persistence and treatment discontinuations due to adverse events (AEs), at 96 (±24) weeks after treatment initiation.
Results: Of 2359 participants, DTG/3TC was prescribed in 472 (20.0%), bictegravir/tenofovir alafenamide (TAF)/emtricitabine (FTC) in 1134 (48.1%), DTG + tenofovir disoproxil fumarate/FTC in 300 (12.7%), DTG/abacavir/3TC in 273 (11.6%) and darunavir/cobicistat/TAF/FTC in 180 (7.6%). At 96 weeks from treatment initiation, 94.0% of participants initiating with DTG/3TC achieved VS, and the mean increase in CD4 cell counts was 295.5 cells/μL (95% CI: 269.9-321.1). During the first 96 weeks after DTG/3TC initiation, 9.8% and 1.3% discontinued their initial regimen, overall and due to AEs, respectively. In multivariable analyses, we did not find significant differences in VS or increase in CD4 cell counts among participants initiating with DTG/3TC compared with other regimens. Initiating ART with a regimen other than DTG/3TC was associated with a higher risk of treatment discontinuation, overall and due to AEs.
Conclusions: Among treatment-naive people with HIV from this large multicentre cohort, DTG/3TC had similar effectiveness and better persistence and tolerability than those of the most frequently prescribed first-line regimens at 96 weeks.
{"title":"Long-term effectiveness and tolerability of dolutegravir/lamivudine in treatment-naive people with HIV: an analysis of a multicentre cohort at 96 weeks.","authors":"Inés Suárez-García, Belén Alejos, Cristina Moreno, Juan Martín Torres, Mar Masiá, Lucio J García-Fraile, Melchor Riera, David Dalmau, Rafael Rodríguez-Rosado, Roberto Muga, Santiago Moreno, Inma Jarrín","doi":"10.1093/jac/dkae456","DOIUrl":"10.1093/jac/dkae456","url":null,"abstract":"<p><strong>Objectives: </strong>To evaluate the long-term effectiveness, persistence and tolerability of dolutegravir (DTG)/lamivudine (3TC), compared with the most frequently prescribed first-line treatment regimens, among antiretroviral-naive people with HIV from CoRIS, a multicentre cohort in Spain, in 2018-23.</p><p><strong>Methods: </strong>We used multivariable regression models to compare viral suppression (VS) (HIV RNA viral load <50 copies/mL), change in CD4 cell counts, persistence and treatment discontinuations due to adverse events (AEs), at 96 (±24) weeks after treatment initiation.</p><p><strong>Results: </strong>Of 2359 participants, DTG/3TC was prescribed in 472 (20.0%), bictegravir/tenofovir alafenamide (TAF)/emtricitabine (FTC) in 1134 (48.1%), DTG + tenofovir disoproxil fumarate/FTC in 300 (12.7%), DTG/abacavir/3TC in 273 (11.6%) and darunavir/cobicistat/TAF/FTC in 180 (7.6%). At 96 weeks from treatment initiation, 94.0% of participants initiating with DTG/3TC achieved VS, and the mean increase in CD4 cell counts was 295.5 cells/μL (95% CI: 269.9-321.1). During the first 96 weeks after DTG/3TC initiation, 9.8% and 1.3% discontinued their initial regimen, overall and due to AEs, respectively. In multivariable analyses, we did not find significant differences in VS or increase in CD4 cell counts among participants initiating with DTG/3TC compared with other regimens. Initiating ART with a regimen other than DTG/3TC was associated with a higher risk of treatment discontinuation, overall and due to AEs.</p><p><strong>Conclusions: </strong>Among treatment-naive people with HIV from this large multicentre cohort, DTG/3TC had similar effectiveness and better persistence and tolerability than those of the most frequently prescribed first-line regimens at 96 weeks.</p>","PeriodicalId":14969,"journal":{"name":"Journal of Antimicrobial Chemotherapy","volume":" ","pages":"682-691"},"PeriodicalIF":3.9,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11879157/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142876948","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Minh-Vu H Nguyen, Vinicius Calado Nogueira de Moura, Tiffany R Keepers, Jakko van Ingen, Charles L Daley
Background: Mycobacterium abscessus is a highly drug-resistant non-tuberculous mycobacterium (NTM) for which treatment is limited by the lack of active oral antimycobacterials and frequent adverse reactions. Epetraborole is a novel oral, boron-containing antimicrobial that inhibits bacterial leucyl-tRNA synthetase, an essential enzyme in protein synthesis, and has been shown to have anti-M. abscessus activity in preclinical studies.
Objectives: To determine epetraborole MIC distribution for 147 recent M. abscessus isolates via broth microdilution.
Methods: M. abscessus isolates collected in 2021 from the USA (n = 122) from pulmonary sources and during 2019-22 predominantly from Europe (n = 25) from pulmonary and extrapulmonary sources had MICs determined by broth microdilution according to CLSI guidelines for epetraborole and a panel of 12 other antimycobacterials. Descriptive analyses were done on the MIC values.
Results: Of the 147 M. abscessus isolates, 101 were subspecies abscessus, 6 were bolletii and 40 were massiliense. Epetraborole MICs ranged from 0.03 to 0.25 mg/L and were consistent across subspecies. Epetraborole MIC50/MIC90 for all isolates were 0.06/0.12 mg/L. When stratified by subspecies, amikacin resistance, clarithromycin resistance and morphotype, the MIC50/MIC90 values remained 0.06/0.12 mg/L.
Conclusions: Epetraborole demonstrated potent in vitro activity against M. abscessus with MICs from 0.03 to 0.25 mg/L and consistent activity against all subspecies, resistance phenotypes and morphotypes. These data support clinical evaluation of epetraborole as a therapeutic option for M. abscessus disease.
{"title":"In vitro susceptibility of 147 international clinical Mycobacterium abscessus isolates to epetraborole and comparators by broth microdilution.","authors":"Minh-Vu H Nguyen, Vinicius Calado Nogueira de Moura, Tiffany R Keepers, Jakko van Ingen, Charles L Daley","doi":"10.1093/jac/dkae461","DOIUrl":"10.1093/jac/dkae461","url":null,"abstract":"<p><strong>Background: </strong>Mycobacterium abscessus is a highly drug-resistant non-tuberculous mycobacterium (NTM) for which treatment is limited by the lack of active oral antimycobacterials and frequent adverse reactions. Epetraborole is a novel oral, boron-containing antimicrobial that inhibits bacterial leucyl-tRNA synthetase, an essential enzyme in protein synthesis, and has been shown to have anti-M. abscessus activity in preclinical studies.</p><p><strong>Objectives: </strong>To determine epetraborole MIC distribution for 147 recent M. abscessus isolates via broth microdilution.</p><p><strong>Methods: </strong>M. abscessus isolates collected in 2021 from the USA (n = 122) from pulmonary sources and during 2019-22 predominantly from Europe (n = 25) from pulmonary and extrapulmonary sources had MICs determined by broth microdilution according to CLSI guidelines for epetraborole and a panel of 12 other antimycobacterials. Descriptive analyses were done on the MIC values.</p><p><strong>Results: </strong>Of the 147 M. abscessus isolates, 101 were subspecies abscessus, 6 were bolletii and 40 were massiliense. Epetraborole MICs ranged from 0.03 to 0.25 mg/L and were consistent across subspecies. Epetraborole MIC50/MIC90 for all isolates were 0.06/0.12 mg/L. When stratified by subspecies, amikacin resistance, clarithromycin resistance and morphotype, the MIC50/MIC90 values remained 0.06/0.12 mg/L.</p><p><strong>Conclusions: </strong>Epetraborole demonstrated potent in vitro activity against M. abscessus with MICs from 0.03 to 0.25 mg/L and consistent activity against all subspecies, resistance phenotypes and morphotypes. These data support clinical evaluation of epetraborole as a therapeutic option for M. abscessus disease.</p>","PeriodicalId":14969,"journal":{"name":"Journal of Antimicrobial Chemotherapy","volume":" ","pages":"713-716"},"PeriodicalIF":3.9,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11879195/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142907055","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Anna-Karin Smekal, Maria Swartling, Mia Furebring, Christian G Giske, Siv Jönsson, Miklos Lipcsey, Elisabet I Nielsen
Objectives: This study aimed to predict the impact of different infusion strategies on pharmacokinetic/pharmacodynamic (PK/PD) target attainment and the potential risk for toxicity in an ICU cohort treated with β-lactams.
Method: Using collected patient data from 137 adult ICU patients, and applying population PK models, individual PK parameters were estimated and used to predict concentrations and target attainment following cefotaxime 2 g q8h, piperacillin/tazobactam 4.5 g q6h and meropenem 1 g q8h, applying 15 min short infusions (SI), 3 h extended infusions (EI) and 24 h continuous infusion (CI). The MIC level of the most common primary pathogens, and the worst-case scenario (WCS) pathogen, were used in analyses.
Results: For primary pathogens, target was reached in 94% (129/137) using SI. For WCS pathogens treated with piperacillin/tazobactam and meropenem, 78% (65/83) and 92% (76/83) reached target using SI and EI, respectively. However, target attainment was lower for cefotaxime [SI: 31% (17/54), EI: 44% (24/54)]. Overall, the number of individuals with potentially toxic concentrations was low, both in EI (n = 7) and SI (n = 5). For CI and WCS, target was reached in 50% (27/54), 96% (54/56) and 93% (25/27) for cefotaxime, piperacillin/tazobactam and meropenem, respectively.
Conclusions: In a Swedish ICU cohort target attainment rates for primary pathogens were high regardless of infusion strategy. In WCS pathogens, SI was insufficient, suggesting the benefit of routine use of EI or CI. However, for cefotaxime, target attainment remained low also with EI and CI. The use of CI might lead to unnecessarily high concentrations, but well-established toxicity levels are lacking and future studies are warranted.
{"title":"Short, extended and continuous infusion of β-lactams: predicted impact on target attainment and risk for toxicity in an ICU patient cohort.","authors":"Anna-Karin Smekal, Maria Swartling, Mia Furebring, Christian G Giske, Siv Jönsson, Miklos Lipcsey, Elisabet I Nielsen","doi":"10.1093/jac/dkaf013","DOIUrl":"10.1093/jac/dkaf013","url":null,"abstract":"<p><strong>Objectives: </strong>This study aimed to predict the impact of different infusion strategies on pharmacokinetic/pharmacodynamic (PK/PD) target attainment and the potential risk for toxicity in an ICU cohort treated with β-lactams.</p><p><strong>Method: </strong>Using collected patient data from 137 adult ICU patients, and applying population PK models, individual PK parameters were estimated and used to predict concentrations and target attainment following cefotaxime 2 g q8h, piperacillin/tazobactam 4.5 g q6h and meropenem 1 g q8h, applying 15 min short infusions (SI), 3 h extended infusions (EI) and 24 h continuous infusion (CI). The MIC level of the most common primary pathogens, and the worst-case scenario (WCS) pathogen, were used in analyses.</p><p><strong>Results: </strong>For primary pathogens, target was reached in 94% (129/137) using SI. For WCS pathogens treated with piperacillin/tazobactam and meropenem, 78% (65/83) and 92% (76/83) reached target using SI and EI, respectively. However, target attainment was lower for cefotaxime [SI: 31% (17/54), EI: 44% (24/54)]. Overall, the number of individuals with potentially toxic concentrations was low, both in EI (n = 7) and SI (n = 5). For CI and WCS, target was reached in 50% (27/54), 96% (54/56) and 93% (25/27) for cefotaxime, piperacillin/tazobactam and meropenem, respectively.</p><p><strong>Conclusions: </strong>In a Swedish ICU cohort target attainment rates for primary pathogens were high regardless of infusion strategy. In WCS pathogens, SI was insufficient, suggesting the benefit of routine use of EI or CI. However, for cefotaxime, target attainment remained low also with EI and CI. The use of CI might lead to unnecessarily high concentrations, but well-established toxicity levels are lacking and future studies are warranted.</p>","PeriodicalId":14969,"journal":{"name":"Journal of Antimicrobial Chemotherapy","volume":" ","pages":"876-884"},"PeriodicalIF":3.9,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11879237/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143028838","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Resistance profiles of carbapenemase-producing Enterobacterales in a large centre in England: are we already losing cefiderocol?-right to reply-authors' response.","authors":"Ioannis Baltas, Trupti Patel, Ana Lima Soares","doi":"10.1093/jac/dkaf061","DOIUrl":"10.1093/jac/dkaf061","url":null,"abstract":"","PeriodicalId":14969,"journal":{"name":"Journal of Antimicrobial Chemotherapy","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143556794","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Tommaso Clemente, Sara Diotallevi, Davide Minisci, Antonio Di Biagio, Riccardo Lolatto, Letizia Attala, Giovanni Cenderello, Alessia Siribelli, Camilla Muccini, Sergio Lo Caputo, Marcello Tavio, Rebecka Papaioannu Borjesson, Andrea Giacomelli, Antonella Castagna, Vincenzo Spagnuolo
Background: Major adverse cardiovascular events (MACEs) may contribute to the high morbidity in people with four-class drug-resistant HIV (4DR-PWH).
Objectives: To explore the probability of MACEs in 4DR-PWH compared with non-4DR controls.
Methods: This was a retrospective, propensity score-matched cohort study on 4DR-PWH (cases) and non-4DR-PWH (controls), on ART, without previous MACEs. Controls were matched with cases in a 4:1 ratio for age, sex-assigned-at-birth and ART duration. Incidence rates (IRs) and incidence rate ratio (IRR) of MACEs with 95% CIs were modelled by Poisson regression. Cumulative probabilities of the first incident MACE were estimated by Kaplan-Meier curves. A multivariable stepwise Cox proportional hazards model estimated predictors of incident MACEs among covariates with univariable P < 0.100.
Results: Overall, 223 4DR-PWH and 797 non-4DR-PWH were evaluated. During a median (IQR) follow-up of 8.2 (5.4-11.1) years [1833 person-years of follow-up (PY)], 23/223 (10.3%) 4DR-PWH developed 29 MACEs, IR = 1.6 (95% CI = 1.1-2.3)/100 PY. During a median follow-up of 8.4 (5.2-11.0) years (6450 PY), 42/797 (5.3%) non-4DR controls had 45 MACEs, IR = 0.7 (95% CI = 0.5-0.9)/100 PY, IRR (4DR/non-4DR) = 2.3 (95% CI = 1.4-3.6). The cumulative probabilities of the first MACE were more than doubled in 4DR-PWH (P = 0.006). At multivariable analysis, an increased risk of MACEs was associated with 4DR status [adjusted hazard ratio (aHR) = 1.9; 95% CI = 1.0-3.4], after adjusting for age, sex-assigned-at-birth, HIV load, CD4+ nadir, total cholesterol, HDL cholesterol, diabetes mellitus, statin use and baseline HCV serostatus.
Conclusions: In PWH, MDR is significantly associated with a higher risk of cardiovascular events. Prompt implementation of prevention strategies is mandatory in this fragile population.
背景:重大心血管不良事件(mace)可能是导致四级耐药HIV (4DR-PWH)患者高发病率的原因之一。目的:探讨与非4dr对照相比,4DR-PWH患者发生mace的概率。方法:这是一项回顾性、倾向评分匹配的队列研究,研究对象为接受ART治疗的4DR-PWH(病例)和非4DR-PWH(对照组),既往无mace。对照组与病例按4:1的年龄、出生时性别和ART持续时间进行匹配。ci为95%的mace的发病率(IRs)和发病率比(IRR)采用泊松回归建模。用Kaplan-Meier曲线估计了第一次事件MACE的累积概率。多变量逐步Cox比例风险模型估计单变量间mace事件的预测因子P < 0.100。结果:总体而言,223例4DR-PWH和797例非4DR-PWH进行了评估。在中位(IQR)随访8.2(5.4-11.1)年[1833人-年随访(PY)]期间,23/223 (10.3%)4DR-PWH发生29例mace, IR = 1.6 (95% CI = 1.1-2.3)/100 PY。在中位随访8.4(5.2-11.0)年(6450 PY)期间,42/797(5.3%)非4DR对照组有45例mace, IR = 0.7 (95% CI = 0.5-0.9)/100 PY, IRR (4DR/非4DR) = 2.3 (95% CI = 1.4-3.6)。第一次MACE的累积概率在4DR-PWH组增加了一倍以上(P = 0.006)。在多变量分析中,mace的风险增加与4DR状态相关[调整风险比(aHR) = 1.9;95% CI = 1.0-3.4],在调整了年龄、出生性别、HIV载量、CD4+最低点、总胆固醇、高密度脂蛋白胆固醇、糖尿病、他汀类药物使用和基线HCV血清状态后。结论:在PWH中,MDR与较高的心血管事件风险显著相关。在这一脆弱人群中,必须迅速实施预防战略。
{"title":"Two-fold increased risk of cardiovascular events in people with MDR HIV: a matched cohort analysis with data from the PRESTIGIO registry.","authors":"Tommaso Clemente, Sara Diotallevi, Davide Minisci, Antonio Di Biagio, Riccardo Lolatto, Letizia Attala, Giovanni Cenderello, Alessia Siribelli, Camilla Muccini, Sergio Lo Caputo, Marcello Tavio, Rebecka Papaioannu Borjesson, Andrea Giacomelli, Antonella Castagna, Vincenzo Spagnuolo","doi":"10.1093/jac/dkae465","DOIUrl":"10.1093/jac/dkae465","url":null,"abstract":"<p><strong>Background: </strong>Major adverse cardiovascular events (MACEs) may contribute to the high morbidity in people with four-class drug-resistant HIV (4DR-PWH).</p><p><strong>Objectives: </strong>To explore the probability of MACEs in 4DR-PWH compared with non-4DR controls.</p><p><strong>Methods: </strong>This was a retrospective, propensity score-matched cohort study on 4DR-PWH (cases) and non-4DR-PWH (controls), on ART, without previous MACEs. Controls were matched with cases in a 4:1 ratio for age, sex-assigned-at-birth and ART duration. Incidence rates (IRs) and incidence rate ratio (IRR) of MACEs with 95% CIs were modelled by Poisson regression. Cumulative probabilities of the first incident MACE were estimated by Kaplan-Meier curves. A multivariable stepwise Cox proportional hazards model estimated predictors of incident MACEs among covariates with univariable P < 0.100.</p><p><strong>Results: </strong>Overall, 223 4DR-PWH and 797 non-4DR-PWH were evaluated. During a median (IQR) follow-up of 8.2 (5.4-11.1) years [1833 person-years of follow-up (PY)], 23/223 (10.3%) 4DR-PWH developed 29 MACEs, IR = 1.6 (95% CI = 1.1-2.3)/100 PY. During a median follow-up of 8.4 (5.2-11.0) years (6450 PY), 42/797 (5.3%) non-4DR controls had 45 MACEs, IR = 0.7 (95% CI = 0.5-0.9)/100 PY, IRR (4DR/non-4DR) = 2.3 (95% CI = 1.4-3.6). The cumulative probabilities of the first MACE were more than doubled in 4DR-PWH (P = 0.006). At multivariable analysis, an increased risk of MACEs was associated with 4DR status [adjusted hazard ratio (aHR) = 1.9; 95% CI = 1.0-3.4], after adjusting for age, sex-assigned-at-birth, HIV load, CD4+ nadir, total cholesterol, HDL cholesterol, diabetes mellitus, statin use and baseline HCV serostatus.</p><p><strong>Conclusions: </strong>In PWH, MDR is significantly associated with a higher risk of cardiovascular events. Prompt implementation of prevention strategies is mandatory in this fragile population.</p>","PeriodicalId":14969,"journal":{"name":"Journal of Antimicrobial Chemotherapy","volume":" ","pages":"731-737"},"PeriodicalIF":3.9,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142894491","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Alioune Wade, Seynabou D Sene, Emanuelle Caspar, Fatoumata Diallo, Lucien Platon, Lucas Thiebaut, Mariama N Pouye, Aboubacar Ba, Laty Gaye Thiam, Magal Fall, Bacary Djilocalisse Sadio, Ife Desamours, Noemi Guerra, Kelly Hagadorn, Alfred Amambua-Ngwa, Amy K Bei, Ines Vigan-Womas, Didier Ménard, Alassane Mbengue
Background: Since 2006, artemisinin-based combination therapies (ACTs) have been introduced in Senegal in response to chloroquine resistance (CQ-R) and have shown high efficacy against Plasmodium falciparum. However, the detection of the PfKelch13R515K mutation in Kaolack, which confers artemisinin resistance in vitro, highlights the urgency of strengthening antimalarial drug surveillance to achieve malaria elimination by 2030.
Objective: To assess the proportion of P. falciparum parasites carrying molecular signatures associated with antimalarial resistance (PfKelch13, Pfmdr1, Pfcrt, dhfr and dhps) in isolates collected at Kédougou using multiplex amplicon deep sequencing.
Methods: Venous blood samples were collected from patients diagnosed with P. falciparum infection over a 3-year period (2021, 2022 and 2023). Parasite DNA was extracted, and multiplex amplicon sequencing was used to investigate gene polymorphisms.
Results: Analysis of PfKelch13 did not reveal any non-synonymous mutations. Pfcrt mutations were present in 45% of the samples, mainly K76T (44%) and I356T (36%). The dominant Pfmdr-1 allele was Y184F (62%). The sextuple mutant 51I/59R/108N + 436A/437G/613S dhfr/dhps was observed in 10% of the samples.
Conclusion: The absence of PfKelch13 mutants suggests that ACT efficacy remains uncompromised, although clinical outcome studies are required to confirm this. Analysis of Pfcrt and Pfmdr-1 shows that CQ-R alleles, probably from previous CQ use, are slowly decreasing. Likewise, the detection of the dhfr/dhps sextuple mutant highlights the need to monitor sulfadoxine-pyrimethamine resistance and the emergence of 581G. There is therefore a need for continued antimalarial resistance surveillance in Senegal.
{"title":"Monitoring molecular markers associated with antimalarial drug resistance in south-east Senegal from 2021 to 2023.","authors":"Alioune Wade, Seynabou D Sene, Emanuelle Caspar, Fatoumata Diallo, Lucien Platon, Lucas Thiebaut, Mariama N Pouye, Aboubacar Ba, Laty Gaye Thiam, Magal Fall, Bacary Djilocalisse Sadio, Ife Desamours, Noemi Guerra, Kelly Hagadorn, Alfred Amambua-Ngwa, Amy K Bei, Ines Vigan-Womas, Didier Ménard, Alassane Mbengue","doi":"10.1093/jac/dkaf006","DOIUrl":"10.1093/jac/dkaf006","url":null,"abstract":"<p><strong>Background: </strong>Since 2006, artemisinin-based combination therapies (ACTs) have been introduced in Senegal in response to chloroquine resistance (CQ-R) and have shown high efficacy against Plasmodium falciparum. However, the detection of the PfKelch13R515K mutation in Kaolack, which confers artemisinin resistance in vitro, highlights the urgency of strengthening antimalarial drug surveillance to achieve malaria elimination by 2030.</p><p><strong>Objective: </strong>To assess the proportion of P. falciparum parasites carrying molecular signatures associated with antimalarial resistance (PfKelch13, Pfmdr1, Pfcrt, dhfr and dhps) in isolates collected at Kédougou using multiplex amplicon deep sequencing.</p><p><strong>Methods: </strong>Venous blood samples were collected from patients diagnosed with P. falciparum infection over a 3-year period (2021, 2022 and 2023). Parasite DNA was extracted, and multiplex amplicon sequencing was used to investigate gene polymorphisms.</p><p><strong>Results: </strong>Analysis of PfKelch13 did not reveal any non-synonymous mutations. Pfcrt mutations were present in 45% of the samples, mainly K76T (44%) and I356T (36%). The dominant Pfmdr-1 allele was Y184F (62%). The sextuple mutant 51I/59R/108N + 436A/437G/613S dhfr/dhps was observed in 10% of the samples.</p><p><strong>Conclusion: </strong>The absence of PfKelch13 mutants suggests that ACT efficacy remains uncompromised, although clinical outcome studies are required to confirm this. Analysis of Pfcrt and Pfmdr-1 shows that CQ-R alleles, probably from previous CQ use, are slowly decreasing. Likewise, the detection of the dhfr/dhps sextuple mutant highlights the need to monitor sulfadoxine-pyrimethamine resistance and the emergence of 581G. There is therefore a need for continued antimalarial resistance surveillance in Senegal.</p>","PeriodicalId":14969,"journal":{"name":"Journal of Antimicrobial Chemotherapy","volume":" ","pages":"828-839"},"PeriodicalIF":3.9,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11879165/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143023569","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Samuel Bungaran Partahi Saud Manalu, Andrea Perez Navarro, Cassandra Fairhead, Andrew Hill
Background: In 2023, there were 39.9 million people living with HIV (PLWH) worldwide and 630 000 deaths related to HIV. New strategies are needed, and long-acting antiretrovirals (LAAs) are now widely considered to have great potential to help end the HIV epidemic. This systematic review and meta-analysis compare the safety and efficacy of LAA versus standard oral treatment (SOT) for HIV.
Methods: PubMed and Embase databases, supplemented by ClinicalTrials.gov and grey literature, were searched. Randomized controlled trials (RCTs) reporting efficacy and/or safety of LAA versus SOT for PLWH until June 2024 were included. Efficacy (HIV RNA < 50 copies/mL) and HIV RNA ≥ 50 copies/mL, adverse events (AEs), treatment discontinuation, CD4 count, metabolic parameters and drug resistance were assessed. Prespecified subgroup analyses were conducted. The risk of bias was assessed with Cochrane RoB 2.0. Certainty of evidence was assessed using GRADE.
Results: Six RCTs were eligible for inclusion, involving 2829 participants. LAA was non-inferior to SOT in suppressing HIV RNA < 50 copies/mL [Risk Difference (RD), -0.00; 95% CI, -0.03-0.02; P = 0.83; I2 = 51%; high quality of evidence (QoE)]. LAA was associated with higher drug resistance (percentage pooled estimate, 57%; 95% CI, 33%-78% versus 9%; 95% CI, 2%-30%; moderate QoE) and risk of grade 1-4 AEs than SOT [Risk Ratio (RR), 1.22; 95% CI, 1.12-1.33; P < 0.001; I2 = 62%; moderate QoE].
Conclusions: LAA has non-inferior efficacy compared to SOT. However, participants receiving LAA were at a higher risk of developing drug resistance, cross-resistance and AEs.
{"title":"Safety and efficacy of long-acting cabotegravir/rilpivirine versus standard oral antiretroviral therapy: a systematic review and meta-analysis.","authors":"Samuel Bungaran Partahi Saud Manalu, Andrea Perez Navarro, Cassandra Fairhead, Andrew Hill","doi":"10.1093/jac/dkae480","DOIUrl":"10.1093/jac/dkae480","url":null,"abstract":"<p><strong>Background: </strong>In 2023, there were 39.9 million people living with HIV (PLWH) worldwide and 630 000 deaths related to HIV. New strategies are needed, and long-acting antiretrovirals (LAAs) are now widely considered to have great potential to help end the HIV epidemic. This systematic review and meta-analysis compare the safety and efficacy of LAA versus standard oral treatment (SOT) for HIV.</p><p><strong>Methods: </strong>PubMed and Embase databases, supplemented by ClinicalTrials.gov and grey literature, were searched. Randomized controlled trials (RCTs) reporting efficacy and/or safety of LAA versus SOT for PLWH until June 2024 were included. Efficacy (HIV RNA < 50 copies/mL) and HIV RNA ≥ 50 copies/mL, adverse events (AEs), treatment discontinuation, CD4 count, metabolic parameters and drug resistance were assessed. Prespecified subgroup analyses were conducted. The risk of bias was assessed with Cochrane RoB 2.0. Certainty of evidence was assessed using GRADE.</p><p><strong>Results: </strong>Six RCTs were eligible for inclusion, involving 2829 participants. LAA was non-inferior to SOT in suppressing HIV RNA < 50 copies/mL [Risk Difference (RD), -0.00; 95% CI, -0.03-0.02; P = 0.83; I2 = 51%; high quality of evidence (QoE)]. LAA was associated with higher drug resistance (percentage pooled estimate, 57%; 95% CI, 33%-78% versus 9%; 95% CI, 2%-30%; moderate QoE) and risk of grade 1-4 AEs than SOT [Risk Ratio (RR), 1.22; 95% CI, 1.12-1.33; P < 0.001; I2 = 62%; moderate QoE].</p><p><strong>Conclusions: </strong>LAA has non-inferior efficacy compared to SOT. However, participants receiving LAA were at a higher risk of developing drug resistance, cross-resistance and AEs.</p>","PeriodicalId":14969,"journal":{"name":"Journal of Antimicrobial Chemotherapy","volume":" ","pages":"624-632"},"PeriodicalIF":3.9,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11879206/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142949166","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Correction to: Major role of dolutegravir in the emergence of the S147G integrase resistance mutation.","authors":"","doi":"10.1093/jac/dkaf014","DOIUrl":"10.1093/jac/dkaf014","url":null,"abstract":"","PeriodicalId":14969,"journal":{"name":"Journal of Antimicrobial Chemotherapy","volume":" ","pages":"895"},"PeriodicalIF":3.9,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143005898","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}