Toscana virus (TOSV) is a Phlebotomus-transmitted RNA virus and a frequent cause of human meningitis and meningoencephalitis in Southern Europe during the summer season. While evidence for ...TOSV-related central nervous system (CNS) cases is increasing, little is known about the host defenses against TOSV. We evaluated innate immune response to TOSV by analyzing frequency and activation of blood antigen-presenting cells (APCs) and cytokine levels in plasma and cerebrospinal fluid (CSF) from patients with TOSV neuroinvasive infection and controls. An altered frequency of different blood APC subsets was observed in TOSV-infected patients, with signs of monocytic deactivation. Nevertheless, a proper or even increased responsiveness of toll-like receptor 3 and 7/8 was observed in blood APCs of these patients as compared to healthy controls. Systemic levels of cytokines remained low in TOSV-infected patients, while levels of anti-inflammatory and antiviral mediators were significantly higher in CSF from TOSV-infected patients as compared to patients with other infectious and noninfectious neurological diseases. Thus, the early host response to TOSV appears effective for viral clearance, by proper response to TLR3 and TLR7/8 agonists in peripheral blood and by a strong and selective antiviral and anti-inflammatory response in the CNS.
•Doravirine (DOR) resistance is uncommon among non-nucleoside reverse transcriptase inhibitor (NNRTI)-experienced patients.•Complete DOR resistance in NNRTI-experienced patients is mainly related to ...Y188L mutation.•Previous efavirenz and etravirine use are associated with detection of DOR resistance.•Previous rilpivirine use is associated with a lower probability of DOR resistance.
This study investigated the prevalence of doravirine (DOR) resistance mutations in non-nucleoside reverse transcriptase inhibitor (NNRTI)-experienced patients. DOR resistance was assessed in samples from NNRTI-experienced patients who underwent genotypic testing for virological failure from the Antiretroviral Response Cohort Analysis (ARCA) database. Intermediate DOR resistance was defined as detection of any of V106A/M, Y188C/H, V108I, and K103N+P225H. High-level DOR resistance was defined as detection of any of Y188L, M230L, G190E, V106A/M+F227L, and V106A/M+L234I. Overall, 6893 patients were included in the study: 64.2% had experienced efavirenz (EFV), 54.4% nevirapine (NVP), 6.8% etravirine (ETR), 7.7% rilpivirine (RPV) and 0.7% delavirdine. Among NNRTI-experienced patients, 12.7% and 6.1% of subjects had intermediate and high-level DOR resistance, respectively. The most common DOR resistance mutation was Y188L. In multivariable analysis, previous EFV use (OR = 1.52, 95% CI 1.15–2.02) and ETR use (OR = 1.91, 95% CI 1.34–2.73) were associated with detection of high-level DOR resistance, whilst RPV use was associated with a lower probability of high-level DOR resistance (OR = 0.39, 95% CI 0.22–0.71). Moreover, EFV use (OR = 1.76, 95% CI 1.19–2.58) and ETR use (OR = 1.72, 95% CI 1.10–2.68) were associated with detection of the Y188L mutation, whereas RPV use was not (OR = 0.16, 95% CI 0.05–0.50). In Italy, DOR resistance is uncommon among NNRTI-experienced patients, confirming a distinguishing resistance pattern within NNRTIs. However, previous EFV and ETR experience poses a higher risk of DOR resistance. These results support the use of DOR in NNRTI-experienced patients.
Objectives
The aim was to evaluate the evolution of transmitted HIV‐1 drug resistance (TDR) prevalence in antiretroviral therapy (ART)‐naïve patients from 2006 to 2016.
Methods
HIV‐1 sequences were ...retrieved from the Antiviral Response Cohort Analysis (ARCA) database and TDR was defined as detection of at least one mutation from the World Health Organization (WHO) surveillance list.
Results
We included protease/reverse transcriptase sequences from 3573 patients; 455 had also integrase sequences. Overall, 68.1% of the patients were Italian, the median CD4 count was 348 cells/μL interquartile range (IQR) 169–521 cells/μL, and the median viral load was 4.7 log10 HIV‐1 RNA copies/mL (IQR 4.1–5.3 log10 copies/mL). TDR was detected in 10.3% of patients: 6% carried mutations to nucleos(t)ide reverse transcriptase inhibitors (NRTIs), 4.4% to nonnucleos(t)ide reverse transcriptase inhibitors (NNRTIs), 2.3% to protease inhibitors (PIs), 0.2% to integrase strand transfer inhibitors (INSTIs) and 2.1% to at least two drug classes. TDR declined from 14.5% in 2006 to 7.3% in 2016 (P = 0.003): TDR to NRTIs from 9.9 to 2.9% (P = 0.003) and TDR to NNRTIs from 5.1 to 3.7% (P = 0.028); PI TDR remained stable. The proportion carrying subtype B virus declined from 76.5 to 50% (P < 0.001). The prevalence of TDR was higher in subtype B vs. non‐B (12.6 vs. 4.9%, respectively; P < 0.001) and declined significantly in subtype B (from 17.1 to 8.8%; P = 0.04) but not in non‐B subtypes (from 6.1 to 5.8%; P = 0.44). Adjusting for country of origin, predictors of TDR were subtype B adjusted odds ratio (AOR) for subtype B vs. non‐B 2.91; 95% confidence interval (CI) 1.93–4.39; P < 0.001, lower viral load (per log10 higher: AOR 0.86; 95% CI 0.75–0.99; P = 0.03), site in northern Italy (AOR for southern Italy/island vs. northern Italy, 0.61; 95% CI 0.40–0.91; P = 0.01), and earlier calendar year (per 1 year more recent: AOR 0.95; 95% CI 0.91–0.99; P = 0.02).
Conclusions
The prevalence of HIV‐1 TDR has declined during the last 10 years in Italy.
Dual therapy (DT) with boosted protease inhibitors (bPIs) plus lamivudine has been shown to be superior to bPI monotherapy in virologically suppressed patients despite previous selection of the ...lamivudine resistance M184V mutation. We compared the virological efficacy of lamivudine-based DT in patients with and without a history of M184V detection.
We retrospectively analyzed patients with HIV-RNA ≤50 copies/mL switching to DT with at least 1 previous resistance genotype in the ARCA database. Time to virological failure (VF; HIV-RNA ≥200 copies/mL or 2 consecutive HIV-RNA >50 copies/mL) and to treatment discontinuation (TD) was analyzed by survival analysis.
Four hundred thirty-six patients switching to lamivudine plus bPIs (70%) or integrase inhibitors (30%) were included. Patients with M184V (n = 87) were older, had lower nadir CD4+ cell count, longer duration of antiretroviral therapy and of virologic suppression, and higher rate of hepatitis C virus infection compared with patients without M184V. The 3-year probability of remaining free from VF was 91.9% (95% confidence interval CI, 86.6-97.2) without M184V and 87.8% (95% CI, 78.4-97.2) with M184V (
= .323). The time to TD did not differ between groups. Multivariate analysis adjusting for baseline variables differing between groups also did not detect M184V as being associated with VF or TD; however, the 3-year probability of remaining free of viral blips (isolated HIV-RNA 51-199 copies/mL) was 79.8% (95% CI, 67.8%-91.8%) with M184V vs 90.1% (95% CI, 84.0%-96.2%) without M184V (
= .016).
Previous selection of M184V did not increase the risk of VF or TD with lamivudine-based DT but was associated with a higher probability of viral blips.
Acute bacterial meningitis is a rare but extremely severe disease. The aim of this study was to investigate whether neutrophil gelatinase-associated lipocalin (NGAL) is present and measurable in ...cerebrospinal fluid (CSF) and if its assessment may be useful for identifying patients with bacterial meningitis.
Eligible specimens were all consecutive CSFs of patients with suspect acute bacterial meningitis that were referred from the Unit of Infectious Diseases for routine chemical and morphological analysis over a three months period. CSF measurements consisted in NGAL, glucose, and total protein concentrations, along with cell count and differential.
Eighty eight CSFs were received throughout the study period, 58 (66%) with CSF findings compatible with bacterial meningitis. The values of white blood cells (WBC), polymorphonuclear (PMN) and mononuclear (MONO) leukocytes, red blood cells (RBC), total proteins, and NGAL were significantly increased in positive CSFs, whereas that of glucose did not significantly differ. A significant correlation was found between CSF concentration of NGAL and CSF values of PMN, WBC, RBC and total proteins, but not with that of glucose and MONO. The concentration of NGAL in CSF showed an area under the curve (AUC) of 0.94 for identifying positive CSFs, with specificity and sensitivity of 1.00 and 0.741 at a diagnostic threshold of 13 ng/mL.
NGAL is present in CSF of patients with bacterial meningitis and its measurement may be helpful for identifying positive CSFs.
Background and objectives
Guidelines indicate a plasma HIV-1 RNA load of 500-1000 copies/mL as the minimal threshold for antiretroviral drug resistance testing. Resistance testing at lower viral load ...levels may be useful to guide timely treatment switches, although data on the clinical utility of this remain limited. We report here the influence of viral load levels on the probability of detecting drug resistance mutations (DRMs) and other mutations by routine genotypic testing in a large multicentre European cohort, with a focus on tests performed at a viral load <1000 copies/mL.
Methods
A total of 16 511 HIV-1 reverse transcriptase and protease sequences from 11 492 treatment-experienced patients were identified, and linked to clinical data on viral load, CD4 T cell counts and antiretroviral treatment history. Test results from 3162 treatment-naive patients served as controls. Multivariable analysis was employed to identify predictors of reverse transcriptase and protease DRMs.
Results
Overall, 2500/16 511 (15.14%) test results were obtained at a viral load <1000 copies/mL. Individuals with viral load levels of 1000-10 000 copies/mL showed the highest probability of drug resistance to any drug class. Independently from other measurable confounders, treatment-experienced patients showed a trend for DRMs and other mutations to decrease at viral load levels <500 copies/mL.
Conclusions
Genotypic testing at low viral load may identify emerging antiretroviral drug resistance at an early stage, and thus might be successfully employed in guiding prompt management strategies that may reduce the accumulation of resistance and cross-resistance, viral adaptive changes, and larger viral load increases.
Correction to: J Transl Med (2020) 18:405 https://doi.org/10.1186/s12967-020-02573-9 Following publication of the original article 1 the authors identified that the collaborators of the TOCIVID-19 ...investigators, Italy were only available in the supplementary file. The original article has been updated so that the collaborators are correctly acknowledged. For clarity, all collaborators are listed in this correction article. Acknowledgement List of participating centres and Co-Investigators TOCIVID-19 Investigators * Istituto Nazionale Tumori, IRCCS, Fondazione G. Pascale, Napoli—Clinical Trials Unit: Francesco Perrone, Maria Carmela Piccirillo, Clorinda Schettino, Adriano Gravina, Piera Gargiulo, Claudia Cardone, Laura Arenare; Melanoma And Cancer Immunotherapy And Developmental Therapeutics Unit: Paolo Antonio Ascierto, Maria Grazia Vitale, Claudia Trojaniello, Marco Palla; Direction: Attilio Antonio Montano Bianchi, Gerardo Botti, Gianfranco De Feo, Leonardo Miscio. * Università degli Studi della Campania Luigi Vanvitelli, Dipartimento di Salute Mentale e Medicina Preventiva; Ciro Gallo, Paolo Chiodini. * IRCCS Policlinico San Donato—Milano: Laurenzia Ferraris, Massimiliano M. Marrocco-Trischitta, Marco Froldi, Lorenzo Menicanti, Maria Teresa Cuppone, Giulia Gobbo, Chiara Baldessari, Vincenzo Valenti, Serenella Castelvecchio, Federica Poli, Francesca Giacomazzi, Rosangela Piccinni, Maria Laura Annnunziata, Andrea Biondi, Cecilia Bussolari, Manuel Mazzoleni, Andrea Giachi, Annalisa Filtz, Arianna Manini, Enrico Poletti, Federico Masserini, Francesco Conforti, Gianfranco Gaudiano, Vittoria Favero, Alice Moroni, Tommaso Viva, Fabiana Fancoli, Davide Ferrari, Dario Niro, Marco Resta, Andrea Ballotta, Marco Dei Poli, Marco Ranucci. * ASST Papa Giovanni XXIII—Bergamo: Diego Ripamonti, Francesca Binda, Alessandra Tebaldi, Giuseppe Gritti, Luisa Pasulo, Leonardo Gaglio, Roberto Del Fabbro, Leonardo Alborghetti. * ASST Monza—Monza: Paolo Bonfanti, Nicola Squillace, Giulia Giustinetti, Paola Columpsi, Marina Cazzaniga, Serena Capici, Luca Sala, Riccardo Di Sciacca, Giacomo Mosca, Maria Rosa Pirozzi. * ASST degli Spedali Civili di Brescia e Università di Brescia—Brescia: Francesco Castelli, Maria Lorenza Muiesan, Franco Franceschini, Aldo Roccaro, Massimo Salvetti, Anna Paini, Luciano Corda, Chiara Ricci, Lina Tomasoni, Paola Nasta, Silvia Lorenzotti, Silvia Odolini, Emanuele Focà, Eugenia Quiros Roldan, Marco Metra, Stefano Magrini, Paolo Borghetti, Nicola Latronico, Simone Piva, Matteo Filippini, Gabriele Tomasoni, Francesco Zuccalà, Sergio Cattaneo, Francesco Scolari, Nicola Bossini, Mario Gaggiotti, Martina Properzi. * Ospedale Santa Maria Goretti—Latina: Miriam Lichtner, Emanuela Del Giudice, Raffaella Marocco, Anna Carraro, Cosmo Del Borgo, Raffaella Marocco, Valeria Belvisi, Tiziana Tieghi, Margherita De Masi, Paola Zuccalà, Paolo Fabietti, Angelo Vetica, Vito Sante Mercurio, Anna Carraro, Laura Fondaco, Blerta Kertusha, Ambrogio Curtolo, Emanuela Del Giudice, Riccardo Lubrano, Maria Gioconda Zotti, Antonella Puorto, Marcello Ciuffreda, Antonella Sarni, Gabriella Monteforte, Domenico Romeo, Emanuela Viola, Carla Damiani, Antonietta Barone, Barbara Mantovani, Daniela Di Sanzo, Vincenzo Gentili, Massimo Carletti, Massimo Aiuti, Andrea Gallo, Piero Giuseppe Meliante, Salvatore Martellucci, Oliviero Riggio, Vincenzo Cardinale, Lorenzo Ridola, Maria Consiglia Bragazzi, Stefania Gioia, Emiliano Valenzi, Camilla Graziosi, Niccolò Bina, Martina Fasolo, Silvano Ricci, Maria Teresa Gioacchini, Antonella Lucci, Luisella Corso, Daniela Tornese, Parni Nijhawan, Francesco Equitani, Carmine Cosentino, Marcello Palladino, Frida Leonetti, Gaetano Leto, Camillo Gnessi, Giuseppe Campagna, Roberto Cesareo, Francesca Marrocco, Giuseppe Straface, Alessandra Mecozzi, Lidia Cerbo, Valentina Isgrò, Sergio Parrocchia, Giuseppe Visconti, Giorgio Casati. * AOU di Parma—Parma: Carlo Calzetti, Alarico Ariani, Lorenzo Donghi. * AOUI di Verona—Verona: Nicola Duccio Salerno, Evelina Tacconelli, Marco Bertoldi, Paolo Cattaneo, Lorenza Lambertenghi, Leonardo Motta, Luca Omega. * Humanitas Gavazzeni—Bergamo: Giovanni Albano. * AORN Dei Colli—Napoli: Roberto Parrella, Fiorentino Fraganza, Luigi Atripaldi, Vincenzo Montesarchio, Francesco Scarano, Annunziata De Rosa, Amalia Buglione, Sabrina Lavoretano, Gianfranco Gaglione, Mario De Marco, Vincenzo Sangiovanni, Francesco Maria Fusco, Rosaria Viglietti, Elio Manzillo, Carolina Rescigno, Raffaella Pisapia, Giulia Plamieri, Alberto Maraolo, Giosuè Calabria, Mario Catalano, Giuseppe Fiorentino, Anna Annunziata, Giorgio Polistina, Pasquale Imitazione, Mariano Mollica, Vincenzo Esposito, Maurizio D’Abraccio, Rodolfo Punzi, Vincenzo Bianco, Costanza Sbreglia. * Azienda Ospedaliera Umberto I—Siracusa: Rosa Fontana Del Vecchio, Alessandro Bordonali, Antonina Franco. * Arcispedale Santa Maria Nuova IRCCS—Reggio Emilia: Carlo Salvarani, Marco Massari, Giovanni Dolci, Pierpaolo Salsi, Matteo Fontana. * ASST di Cremona—Cremona: Giuseppe Virzì, Calderone Ornella, Alfredo Molteni. * Azienda Ospedaliera San Salvatore—Pesaro: Silvia Gennarini, Umberto Gnudi, Maria Anastasia Ricci, Giancarlo Titolo, Giulio Mensi, Pietro Vuotto, Beatrice Gasperini, Mauro Mancini, Zeno Pasquini. * Ospedale Bassini—Cinisello Balsamo: Paolo Spanu, Stefano Clementi, Simona Pierini, Daniela Bokor, Daniela Gori, Morena Ciofetti, Marina Caimi, Laura Bettazzi, Elisabetta Allevi, Silvia Furiani, Chiara Capitanio, Bernardino Mastropasqua, Claudio Fara, Grazia Pulitanò, Jun Sebastian Matsuno, Francesca Della Porta, Viola Dolfini, Nebiat Balei Beyene. * ASST Degli Spedali Civili Di Brescia—Brescia: Michela Bezzi, Mauro Novali. * AOU di Bologna—Bologna: Pierluigi Viale, Sara Tedeschi, Renato Pascale. * Policlinico S. Matteo—Pavia: Raffaele Bruno, Alessandro Di Filippo, Michele Sachs, Tiberio Oggionni, Michele Di Stefano, Caterina Mengoli. * Ospedale di Conegliano—Conegliano: Cesarina Facchini, De Nardo Daniele. * Azienda Ospedaliera San Salvatore—Pesaro: Gabriele Frausini, Luciano Mucci, Silvia Tedesco, Rita Girolimetti, Elena Manfredini, Anna Maria Di Carlo, Emma Espinosa, Donatella Dennetta. * AOU di Parma—Parma: Andrea Ticinesi, Tiziana Meschi, Antonio Nouvenne. * Azienda Ospedaliera Ordine Mauriziano—Torino: Norbiato Claudio, Francesco Vitale, Marta Saracco. * Ospedale Guglielmo Da Saliceto—Piacenza: Mauro Codeluppi, Elisa Fronti, Patrizia Ferrante. * Ospedale di Fermo—Fermo: Giorgio Amadio Nespola. * AOU di Perugia—Perugia: Daniela Francisci, Andrea Tosti. * Casa Sollievo Della Sofferenza—San Giovanni Rotondo: Cristiano Matteo Carbonelli, Antonio Greco, Maria Giulia Tinti. * Fondazione Poliambulanza Istituto Ospedaliero—Brescia: Roberto Stellini, Camilla Appiani, Piera Reghenzi. * Ospedale Morgagni-Pierantoni—Forlì: Venerino Poletti, Claudia Ravaglia. * Ospedale Area Aretina Nord—Arezzo: Danilo Tacconi, Costanza Malcontenti. * AOU “Maggiore della Carità”—Novara: Pier Paolo Sainaghi, Raffaella Landi, Veronica Vassia, Eleonora Rizzi, Mattia Bellan, Antonella Rossati, Luigi Castello * Policlinico Umberto I—Roma: Claudio Maria Mastroianni, Gianluca Russo. * Presidio Ospedaliero di Jesolo—Jesolo: Toffoletto Fabio, Francesco Saverio Serino, Lucio Brollo, Elena Momesso, Maria Luisa Turati. * ASST Santi Paolo e Carlo—Milano: Antonella D'arminio Monforte, Giulia Marchetti. * Ospedale Civile di Guastalla—Guastalla: Fabrizio Boni, Elisabetta Teopompi, Chiara Trenti, Luca Boracchia, Enrica Minelli, Matteo Fontana, Giulia Ghidoni, Anaflorina Matei, Andrea Caruso. * AO Ospedali Riuniti Villa Sofia e Cervello—Palermo: Giuseppe Arcoleo, Gaetana Camarda, Filippo Catalano, Mario Spatafora. * Ospedale Sacra Famiglia, Fatebenefratelli—Erba: Donato Bettega. * AOU Policlinico Tor Vergata—Roma: Massimo Andreoni, Elisabetta Teti, Loredana Sarmati, Andrea Di Lorenzo, Mariagrazia Celeste. * Ospedali Riuniti Padova Sud—Padova: Fabio Baratto, Jacopo Monticelli, Pietro Criveller. * Ospedale San Paolo—Savona: Antonini Andrea, Anselmo, Riccio. * ASST Spedali Civili Di Brescia—Brescia: Maurizio Castellano, Carlo Cappelli, Federica Corvini, Barbara Zanini. * ASST Spedali Civili Di Brescia, Presidio Ospedaliero Gardone—Brescia: Massimo Crippa, Maurizio Ronconi, Raffaella Costa, Silvia Casella, Loretta Brentana. * Ospedale Civile e Ospedale Dell'Angelo—Mestre: Livio Bernardi, Andrea Frascati, Sandro Panese, Fabio Presotto, Lucio Michieletto, Cristina Bernardi. * Ospedale Santa Maria Delle Croci—Ravenna: Maurizio Fusar. * Presidio Ospedaliero di Cesena—Cesena: Vanni Agnoletti, Martina Farina, Russo. * AOU Careggi—Firenze: Federico Lavorini, Roberta Ginanni. * Istituto Nazionale Malattie Infettive INMI L. Spallanzani, IRCCS—Roma: Fabrizio Palmieri, Silvia Mosti. * Casa Di Cura Beato Palazzolo—Bergamo: Angelo Amaglio, Alessandra Cattaneo. * Istituto Clinico S. Ambrogio Spa—Milano: Silvia Cirri, Andrea Montisci, Chiara Gallazzi, Daniele Cosseta, Barabara Baronio, Lorenzo Rampa. * AO Sant’Anna e San Sebastiano—Caserta: Paolo Maggi, Vincenzo Messina. * Arcispedale Santa Maria Nuova IRCCS—Reggio Emilia: Emanuele Alberto Negri, Chiara Trenti. * Ospedale Generale Provinciale—Macerata: Marialma Berlendis, Maria Cecilia Sabatti. * Azienda Ospedaliera S. Maria—Terni: Michele Palumbo. * ASST Ovest Milanese—Milano: Antonino Mazzone, Paola Faggioli. * Ospedale Bellaria—Bologna: Linda Bussini, Giacomo Fornaro, Francesca Volpato. * Ospedale Maria Vittoria—Torino: Daniele Imperiale, Emilpaolo Manno, Enrico Ferreri, Domenico Martelli, Andrea Verhovez, Silvia Giorgis, Luciana Faccio, Rachele Delli Quadri, Cristina Negro. * Ospedale Giovanni Bosco—Torino: Marcella Converso, Francesca Bosco. * ASST Desenzano Del Garda—Gavardo: Silvia Amadasi, Paolo Prandini, Silvia Cocchi. * Azienda ULSS 6—Vicenza: Vinicio Manfrin, Veronica Del Punta. * PO Sant’Elia—Caltanissetta: Giovanni Mazzola, Giuseppe Sportato. * Ospedale Ca’ Foncello—Treviso: Micaela Romagnoli. * Ospedale Infermi—Rimini: Francesco Cristini
PDF
