Publications by authors named "Stefano Bonora"

244 Publications

Spinning pupil aberration measurement for anisoplanatic deconvolution.

Opt Lett 2021 Jun;46(12):2884-2887

The aberrations in an optical microscope are commonly measured and corrected at one location in the field of view, within the so-called isoplanatic patch. Full-field correction is desirable for high-resolution imaging of large specimens. Here we present, to the best of our knowledge, a novel wavefront detector, based on pupil sampling with subapertures, measuring the aberrated wavefront phase at each position of the specimen. Based on this measurement, we propose a region-wise deconvolution that provides an anisoplanatic reconstruction of the sample image. Our results indicate that the measurement and correction of the aberrations can be performed in a wide-field fluorescence microscope over its entire field of view.
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http://dx.doi.org/10.1364/OL.427518DOI Listing
June 2021

Development and Validation of an Up-to-Date Highly Sensitive UHPLC-MS/MS Method for the Simultaneous Quantification of Current Anti-HIV Nucleoside Analogues in Human Plasma.

Pharmaceuticals (Basel) 2021 May 13;14(5). Epub 2021 May 13.

Department of Medical Sciences, University of Turin, Laboratory of Clinical Pharmacology and Pharmacogenetics, Amedeo di Savoia Hospital, 10149 Turin, Italy.

Therapeutic options to treat HIV infection have widened in the past years, improving both effectiveness and tolerability, but nucleoside reverse transcriptase inhibitors (NRTIs) are still considered the standard backbone of the combination regimens. Therapeutic drug monitoring (TDM) can be useful for these drugs, due to concentration-effect relationship, with risk of ineffectiveness, toxicity or adherence concerns: in this scenario, robust and multiplexed methods are needed for an effective TDM activity. In this work, the first validated ultra-high spectrometry liquid chromatography coupled with tandem mass spectrometry (UHPLC-MS/MS) method is described for the high-sensitive simultaneous quantification of all the currently used NRTIs in human plasma, including tenofovir alafenamide (TAF), following FDA and EMA guidelines. The automated sample preparation consisted in the addition of an internal standard (IS) working solution, containing stable-isotope-linked drugs, protein precipitation and drying. Dry extracts were reconstituted with water, then, these underwent reversed phase chromatographic separation: compounds were detected through electrospray ionization and multiple reaction monitoring. Accuracy, precision, recovery and IS-normalized matrix effect fulfilled guidelines' requirements. The application of this method on samples from people living with HIV (PLWH) showed satisfactory performance, being capable of quantifying the very low concentrations of tenofovir (TFV) in patients treated with TAF.
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http://dx.doi.org/10.3390/ph14050460DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8153023PMC
May 2021

Analytical Validation and Clinical Application of Rapid Serological Tests for SARS-CoV-2 Suitable for Large-Scale Screening.

Diagnostics (Basel) 2021 May 12;11(5). Epub 2021 May 12.

Department of Medical Sciences, University of Torino, 10126 Torino, Italy.

Recently, large-scale screening for COVID-19 has presented a major challenge, limiting timely countermeasures. Therefore, the application of suitable rapid serological tests could provide useful information, however, little evidence regarding their robustness is currently available. In this work, we evaluated and compared the analytical performance of a rapid lateral-flow test (LFA) and a fast semiquantitative fluorescent immunoassay (FIA) for anti-nucleocapsid (anti-NC) antibodies, with the reverse transcriptase real-time PCR assay as the reference. In 222 patients, LFA showed poor sensitivity (55.9%) within two weeks from PCR, while later testing was more reliable (sensitivity of 85.7% and specificity of 93.1%). Moreover, in a subset of 100 patients, FIA showed high sensitivity (89.1%) and specificity (94.1%) after two weeks from PCR. The coupled application for the screening of 183 patients showed satisfactory concordance (K = 0.858). In conclusion, rapid serological tests were largely not useful for early diagnosis, but they showed good performance in later stages of infection. These could be useful for back-tracing and/or to identify potentially immune subjects.
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http://dx.doi.org/10.3390/diagnostics11050869DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8151461PMC
May 2021

Blood-Brain Barrier Impairment in Patients Living with HIV: Predictors and Associated Biomarkers.

Diagnostics (Basel) 2021 May 12;11(5). Epub 2021 May 12.

Department of Medical Sciences, Faculty of Medicine and Surgery, University of Torino, 10126 Torino, Italy.

Despite the substantial changes resulting from the introduction of combination antiretroviral therapy (cART), the prevalence of HIV-associated neurocognitive disorders (HAND) remains substantial. Blood-brain barrier impairment (BBBi) is a frequent feature in people living with HIV (PLWH) and it may persist despite effective antiretroviral treatment. A cross-sectional study was performed in PLWH who underwent lumbar puncture for clinical reasons or research protocols and several cerebrospinal fluid biomarkers were studied. BBBi was defined as cerebrospinal fluid-to-serum albumin ratio (CSAR) >6.5 (<40 years) or >8 (>40 years). We included 464 participants: 147 cART-naïve and 317 on cART. Male sex was prevalent in both groups (72.1% and 72.2% respectively); median age was 44 (38-52) years in naïve and 49 (43-57) years in treated subjects. BBBi was observed in 35.4% naïve and in 22.7% treated participants; the use of integrase inhibitors was associated with a lower prevalence (18.3 vs. 30.9%, = 0.050). At multivariate binary logistic regression (including age and sex) nadir CD4 cell count ( = 0.034), presence of central nervous system (CNS) opportunistic infections ( = 0.024) and cerebrospinal fluid (CSF) HIV RNA ( = 0.002) in naïve participants and male sex ( = 0.021), a history of CNS opportunistic infections ( = 0.001) and CSF HIV RNA ( = 0.034) in treated patients were independently associated with BBBi. CSF cells and neopterin were significantly higher in participants with BBBi. BBBi was prevalent in naïve and treated PLWH and it was associated with CSF HIV RNA and neopterin. Systemic control of viral replication seems to be essential for BBB integrity while sex and treatment influence need further studies.
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http://dx.doi.org/10.3390/diagnostics11050867DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8151579PMC
May 2021

The impact of age on antiretroviral drug pharmacokinetics in the treatment of adults living with HIV.

Expert Opin Drug Metab Toxicol 2021 Jun 29;17(6):665-676. Epub 2021 Apr 29.

Unit of Infectious Diseases, Department of Medical Sciences, University of Torino, Torino, Italy.

Introduction: People living with HIV (PLWH) are aging and will receive life-long treatment: despite substantial improvement in drug efficacy and tolerability, side effects still occur and they can blunt antiretroviral treatment effectiveness. Since age may affect drug exposure and may be associated with side-effects we aimed at reviewing available data on the effect of age on antiretrovirals' pharmacokinetics in adult patients.

Areas Covered: We searched public databases and major conference proceedings for data on age and pharmacokinetics/pharmacodynamics in PLWH. We limited our review to currently used drugs and focused on population pharmacokinetics and physiologically-based pharmacokinetic modeling studies.

Expert Opinion: Available evidence of a potential detrimental effect in elderly PLWH is limited by study design and small sample sizes. Careful consideration of undoubtful benefits and potential harms is advised when prescribing ARVs to geriatric patients and the knowledge of pharmacokinetics changes need to be included in the process. With the 'greying' of the pandemic we need studies with a specific focus on geriatric patients living with HIV that will consider specific phenotypes and associated changes (including sarcopenia).
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http://dx.doi.org/10.1080/17425255.2021.1915285DOI Listing
June 2021

Medication burden and clustering in people living with HIV undergoing therapeutic drug monitoring.

Br J Clin Pharmacol 2021 Apr 22. Epub 2021 Apr 22.

Unit of Infectious Diseases, Department of Medical Sciences, University of Torino, Torino, Italy.

Aim: People living with HIV (PLWH) have a high burden of comorbidities and concomitant medication use. The aim of this study was to analyse the prevalence, predictors and patterns of polypharmacy (PP) in a large therapeutic drug monitoring (TDM) registry.

Methods: We searched our TDM registry and categorized co-medications into 26 drug classes. We included patients with at least one medication recorded: PP and severe polypharmacy (sPP) were defined as the concomitant use of ≥5 or ≥10 nonantiretroviral/nonantitubercular drugs. Multivariable binary logistic analysis were conducted for identifying PP/sPP predictors. A hierarchical average-linkage cluster analysis was performed among drug classes.

Results: We included 2432 participants (1158 PLWH) aged 49.6 years (± 14.4) in the 2016-2020 period. A higher number of concomitant medications (4 vs 3.1, P < .001) and a higher prevalence of PP (26.1% vs 21.8%, P = .015) were recorded in controls. At multivariable binary logistic analysis older age, female gender and HIV-positive serostatus (P = .015) were independent predictors of PP; older age and year of inclusion were independent predictors of sPP. Cluster analysis showed that patients receiving oral drug for type 2 diabetes have a high probability of receiving several other drugs; a cluster of co-medications was observed with opioids, diuretics and central nervous system-affecting drugs.

Conclusion: We observed a moderately high prevalence of polypharmacy in middle-aged PLWH: advanced age and female gender were associated with the greatest prevalence. The observation of co-medication clusters suggests groups of comorbidities but also identifies groups of patients at risk of similar drug-to-drug interactions.
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http://dx.doi.org/10.1111/bcp.14869DOI Listing
April 2021

Lowering SARS-CoV-2 viral load might affect transmission but not disease severity in secondary cases.

Lancet Infect Dis 2021 07 14;21(7):914-915. Epub 2021 Apr 14.

University of Torino, Department of Medical Sciences at the Unit of Infectious Diseases, Amedeo di Savoia Hospital, Torino, Italy.

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http://dx.doi.org/10.1016/S1473-3099(21)00205-XDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8046410PMC
July 2021

On the SARS-CoV-2 "Variolation Hypothesis": No Association Between Viral Load of Index Cases and COVID-19 Severity of Secondary Cases.

Front Microbiol 2021 16;12:646679. Epub 2021 Mar 16.

Unit of Infectious Diseases, Department of Medical Sciences, University of Torino at the "Amedeo di Savoia" Hospital, Turin, Italy.

Emerging evidence supports the "variolation hypothesis" in severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), but the derivative idea that the viral load of index cases may predict disease severity in secondary cases could be unsubstantiated. We assessed whether the prevalence of symptomatic infections, hospitalization, and deaths in household contacts of 2019 novel coronavirus disease (COVID-19) cases differed according to the SARS-CoV-2 PCR cycle threshold (Ct) from nasal-pharyngeal swab at diagnosis of linked index cases. Cross-sectional study on household contacts of COVID-19 cases randomly sampled from all the infections diagnosed in March at our Microbiology Laboratory (Amedeo di Savoia, Turin). Data were retrospectively collected by phone interviews and from the Piedmont regional platform for COVID-19 emergency. Index cases were classified as high (HVl) and low viral load (LVl) according to two exploratory cut-offs of RdRp gene Ct value. Secondary cases were defined as swab confirmed or symptom based likely when not tested but presenting compatible clinical picture. One hundred thirty-two index cases of whom 87.9% symptomatic and 289 household contacts were included. The latter were male and Caucasian in 44.3 and 95.8% of cases, with a median age of 34 years (19-57). Seventy-four were swab confirmed and other 28 were symptom based likely secondary cases. Considering both, the contacts of HVl and LVl did not differ in the prevalence of symptomatic infections nor COVID-19-related hospitalization and death. No difference in median Ct of index cases between symptomatic and asymptomatic, hospitalized and not hospitalized, or deceased and survived secondary cases was found. Negative findings were confirmed after adjusting for differences in time between COVID-19 onset and swab collection of index cases (median 5 days) and after removing pediatric secondary cases. The amount of SARS-CoV-2 of the source at diagnosis does not predict clinical outcomes of linked secondary cases. Considering the impelling release of assays for SARS-CoV-2 RNA exact quantification, these negative findings should inform clinical and public health strategies on how to interpret and use the data.
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http://dx.doi.org/10.3389/fmicb.2021.646679DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8010676PMC
March 2021

Diagnostic SARS-CoV-2 Cycle Threshold Value Predicts Disease Severity, Survival, and Six-Month Sequelae in COVID-19 Symptomatic Patients.

Viruses 2021 02 11;13(2). Epub 2021 Feb 11.

Unit of Infectious Diseases, Department of Medical Sciences, University of Torino at the Amedeo di Savoia Hospital, Corso Svizzera 164, 10149 Torino, Italy.

To date, there is no severe acute respiratory syndrome coronavirus 2-(SARS-CoV-2)-specific prognostic biomarker available. We assessed whether SARS-CoV-2 cycle threshold (Ct) value at diagnosis could predict novel CoronaVirus Disease 2019 (COVID-19) severity, clinical manifestations, and six-month sequelae. Hospitalized and outpatient cases were randomly sampled from the diagnoses of March 2020 and data collected at 6 months by interview and from the regional database for COVID-19 emergency. Patients were stratified according to their RNA-dependent-RNA-polymerase Ct in the nasopharyngeal swab at diagnosis as follows: Group A ≤ 20.0, 20.0 < group B ≤ 28.0, and Group C > 28.0. Disease severity was classified according to a composite scale evaluating hospital admission, worst oxygen support required, and survival. Two hundred patients were included, 27.5% in Groups A and B both, 45.0% in Group C; 90% of patients were symptomatic and 63.7% were hospitalized. The median time from COVID-19 onset to swab collection was five days. Lethality, disease severity, type, and number of signs and symptoms, as well as six-month sequelae distributed inversely among the groups with respect to SARS-CoV-2 Ct. After controlling for confounding, SARS-CoV-2 Ct at diagnosis was still associated with COVID-19-related death ( = 0.023), disease severity ( = 0.023), number of signs and symptoms ( < 0.01), and presence of six-month sequelae ( < 0.01). Early quantification of SARS-CoV-2 may be a useful predictive marker to inform differential strategies of clinical management and resource allocation.
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http://dx.doi.org/10.3390/v13020281DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7917896PMC
February 2021

Rifampicin and Isoniazid Maximal Concentrations are Below Efficacy-associated Thresholds in the Majority of Patients: Time to Increase the Doses?

Int J Antimicrob Agents 2021 Mar 1;57(3):106297. Epub 2021 Feb 1.

Unit of Infectious Diseases, Department of Medical Sciences, University of Torino, Torino, Italy.

Background: The treatment of drug-sensitive tuberculosis (TB) is highly effective; however, many patients have suboptimal drug exposure, which possibly explains treatment failures and selection of resistance. This study aimed to describe the prevalence and determinants of suboptimal maximal concentrations (C) for anti-TB drugs.

Methods: An observational study was conducted in patients receiving first-line anti-TB treatment. At two early time points (T1 and T2), blood samples were withdrawn 2 hours post-dose (C) and drug concentrations were measured. Data were expressed as medians (interquartile ranges).

Results: The study included 199 participants: 72.9% were male and the median age was 39.8 years (27.5-51.4). The median C at T1 and T2 were 7950 ng/mL and 7122 ng/mL (rifampicin), 3260 ng/mL and 3185 ng/mL (isoniazid), 4210 ng/mL and 5742 ng/mL (ethambutol), and 31 008 ng/mL and 30 352 ng/mL (pyrazinamide), respectively. Higher doses/kg and other variables (being born in Italy and female gender for rifampicin, older age and proton pump inhibitor use for isoniazid, female gender and older age for pyrazinamide) were identified by multivariate linear regression analysis. Participants with a higher body mass index received lower doses/kg of all anti-TB drugs. Suboptimal C at T1 and T2 were observed in 60% and 66% (rifampicin), 54% and 55% (isoniazid), 33% and 39% (ethambutol), 20% and 11% (pyrazinamide) of patients. Despite 21% of patients at T1 and 24% at T2 showing two or more drugs with suboptimal exposure, no effect on treatment outcome was observed.

Discussion: The majority of patients receiving first-line anti-TB drugs had low isoniazid and rifampin C. Increased doses or the use of therapeutic drug monitoring in selected patients may be advised.
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http://dx.doi.org/10.1016/j.ijantimicag.2021.106297DOI Listing
March 2021

Early low-molecular-weight heparin administration is associated with shorter time to SARS-CoV-2 swab negativity.

Antivir Ther 2020 ;25(6):327-333

Department of Medical Sciences, University of Turin at the Unit of Infectious Diseases, "Amedeo di Savoia" Hospital, Turin, Italy.

Background: Antiviral and immune-modulating properties of low-molecular-weight heparin (LMWH) against Coronaviridae have been reported by in vitro studies, but no in vivo evidence is yet available. We sought to know whether the timing of prophylactic doses of LMWH during the course of COVID-19 may affect the time to SARS-CoV-2 nasal-oropharyngeal swab negativization.

Methods: Retrospective monocentric cross-sectional study on patients requiring sub-intensive ward admission due to first SARS-CoV-2 infection and undergoing early (EH; within 7 days from COVID-19 signs and symptoms onset) versus delayed prophylactic LMWH (DH; after 7 days). SARS-CoV-2 RNA was measured by reverse transcription real-time PCR according to scheduled time points: first swab after 2 weeks from COVID-19 onset, then at 1-week intervals until negativity.

Results: Time to SARS-CoV-2 swab negativity was shorter in EH (38 patients) compared with DH (55 patients): 22 versus 37 days (P=0.004). The number of confirmative negative swabs in EH was significantly higher compared with DH at week 2 (21.1% versus 3.6%; P=0.017) and 4 (60.0% versus 19.6%; P<0.001). At univariate, EH differed from DH for several disease severity and clinical management parameters. Nevertheless, after accounting for the differences, Cox regression showed early LMWH administration (hazard ratio [HR] 2.91 [1.51, 5.63]; P=0.002) and higher lymphocytes nadir (HR 1.04 [1.01, 1.08]; P=0.020) as predictors of shorter time to swab negativity.

Conclusions: This potential antiviral and/or immune-modulating activity of LMWH needs further in vivo confirmations by randomized controlled trials.
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http://dx.doi.org/10.3851/IMP3377DOI Listing
May 2021

Validation of a UHPLC-MS/MS Method to Quantify Twelve Antiretroviral Drugs within Peripheral Blood Mononuclear Cells from People Living with HIV.

Pharmaceuticals (Basel) 2020 Dec 25;14(1). Epub 2020 Dec 25.

Department of Medical Sciences, University of Turin, Laboratory of Clinical Pharmacology and Pharmacogenetics, Amedeo di Savoia Hospital, 10149 Turin, Italy.

Recently, anti-HIV treatment has achieved high efficacy and tolerability. Nevertheless, few data are available about the intracellular penetration of antiretrovirals, partly due to the technical challenges related to intracellular quantification. This work aimed to validate an ultra-high performance liquid chromatography (UHPLC) tandem mass spectrometry (MS/MS) method for the simultaneous quantification of maraviroc, nevirapine, rilpivirine, dolutegravir, raltegravir, cobicistat, darunavir, ritonavir, atazanavir, efavirenz, elvitegravir, and etravirine within peripheral blood mononuclear cells (PBMCs) and apply it to samples from patients. PBMCs were isolated by density gradient on cell preparation tubes (CPT). Samples were prepared by addition of internal standards (IS), sonication, centrifugation, and drying. Reconstituted extracts underwent chromatographic separation by reversed phase UHPLC and detection was performed by electrospray ionization and multiple reaction monitoring. Method validation followed FDA and EMA guidelines, showing acceptable accuracy, precision, recovery and IS-normalized matrix effect. The application to 56 samples from patients undergoing antiretroviral treatment provided description of intracellular penetration, showing method eligibility for future studies.
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http://dx.doi.org/10.3390/ph14010012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7824452PMC
December 2020

Low Tenofovir Plasma Exposure in HIV Oral Pre-exposure Prophylaxis Recipients with Gastrointestinal Disorders.

Antimicrob Agents Chemother 2020 Oct 26. Epub 2020 Oct 26.

Unit of Infectious Diseases, Department of Medical Sciences, University of Turin, Turin, Italy.

Four pre-exposure prophylaxis (PrEP) users with gastro-intestinal disorders (sleeve gastrectomy, terminal ileitis, celiac disease or chronic diarrhea) and receiving oral tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) were included. Despite a self-reported high adherence, trough plasma tenofovir concentrations (after a supervised intake) were significantly lower than those observed in PrEP recipients without gastrointestinal disorders [21 (±9.1) vs. 138 (±85) ng/mL]. PrEP users with gastrointestinal disorders may need increased TDF doses or alternative prophylactic measures.
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http://dx.doi.org/10.1128/AAC.01902-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7927807PMC
October 2020

Efficient implementation of the Shack-Hartmann centroid extraction for edge computing.

J Opt Soc Am A Opt Image Sci Vis 2020 Oct;37(10):1548-1556

Adaptive optics (AO) is an established technique to measure and compensate for optical aberrations. One of its key components is the wavefront sensor (WFS), which is typically a Shack-Hartmann sensor (SH) capturing an image related to the aberrated wavefront. We propose an efficient implementation of the SH-WFS centroid extraction algorithm, tailored for edge computing. In the edge-computing paradigm, the data are elaborated close to the source (i.e., at the edge) through low-power embedded architectures, in which CPU computing elements are combined with heterogeneous accelerators (e.g., GPUs, field-programmable gate arrays). Since the control loop latency must be minimized to compensate for the wavefront aberration temporal dynamics, we propose an optimized algorithm that takes advantage of the unified CPU/GPU memory of recent low-power embedded architectures. Experimental results show that the centroid extraction latency obtained over spot images up to 700×700 pixels wide is smaller than 2 ms. Therefore, our approach meets the temporal requirements of small- to medium-sized AO systems, which are equipped with deformable mirrors having tens of actuators.
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http://dx.doi.org/10.1364/JOSAA.401376DOI Listing
October 2020

Enhancing care for people living with HIV: current and future monitoring approaches.

Expert Rev Anti Infect Ther 2021 Apr 15;19(4):443-456. Epub 2020 Oct 15.

Infectious Diseases Clinic, San Martino Hospital - IRCCS, Genoa, Italy - Department of Health Sciences, University of Genoa, Genova, Italy.

Introduction: Antiretroviral therapy (ART) is the most significant advance in the medical management of HIV-1 infection. Given the fact that HIV cannot be eradicated from the body, ART has to be indefinitely maintained. New approaches need to be defined for monitoring HIV-infected individuals (PLWHIV), including clinical, virologic, immunological parameters and also ways to collect individual points of view and quality of life.

Areas Covered: We discuss which tests may be used to improve the management of PLWHIV and respond to a comprehensive health demand.

Expert Opinion: Viral load and CD4 counts are well-validated outcome measures and we still need them, but they do not completely depict the health status of PLWHIV. We need to better understand and to apply to clinical practice what happens in sanctuaries, what is the role of HIV DNA, what is the meaning of low-level viremia. Most of these questions do not yet have a definitive response. Further, we need to understand how to modify these variables in order to improve outcomes.Similar points may be raised for immunological measures and for tests exploring the tolerability of drugs. The goal must be the evolution from a viro/immunologic-based to a comprehensive quality-of-health-based evaluation of PLWHIV.
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http://dx.doi.org/10.1080/14787210.2021.1823217DOI Listing
April 2021

Risk for SARS-CoV-2 Infection in Healthcare Workers, Turin, Italy.

Emerg Infect Dis 2021 Jan 6;27(1). Epub 2020 Oct 6.

We measured severe acute respiratory syndrome coronavirus 2 spike protein subunits S1/S2 antibodies by using capillary electrophoresis and a chemiluminescence immunoassay for 5,444 active healthcare workers in Italy. Seroprevalence was 6.9% and higher among participants having contact with patients. Seroconversion was not observed in 37/213 previously infected participants.
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http://dx.doi.org/10.3201/eid2701.203027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7774556PMC
January 2021

Co-infection with other respiratory pathogens in COVID-19 patients.

Clin Microbiol Infect 2021 Feb 19;27(2):297-298. Epub 2020 Aug 19.

Unit of Infectious Diseases, Department of Medical Sciences, University of Torino, Italy.

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http://dx.doi.org/10.1016/j.cmi.2020.08.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7434691PMC
February 2021

A review of the potential mechanisms of neuronal toxicity associated with antiretroviral drugs.

J Neurovirol 2020 10 31;26(5):642-651. Epub 2020 Jul 31.

Department of Medical Sciences, School of Infectious and Tropical Diseases, University of Torino, c/o Amedeo di Savoia Hospital - Corso Svizzera 164, 10169, Torino, Italy.

Highly active antiretroviral treatment has led to unprecedented efficacy and tolerability in people living with HIV. This effect was also observed in the central nervous system with the nowadays uncommon observation of dementias; yet in more recent works milder forms are still reported in 20-30% of optimally treated individuals. The idea of a subclinical neuronal toxicity induced by antiretrovirals has been proposed and was somehow supported by the late-emerging effects associated with efavirenz use. In this manuscript we are reviewing all the potential mechanisms by which antiretroviral drugs have been associated with in vitro, ex vivo, or in vivo toxicity to cells pertaining to the central nervous system (neurons, astrocytes, oligodendrocytes, and endothelial cells). These include direct or indirect effects and pathological pathways such as amyloid deposition, damage to small cerebral vessels, and impairment in neurotransmission. The aim of this review is therefore to provide a detailed description of the available literature in order to guide further clinical research for improving patients' neurocognition and quality of life.
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http://dx.doi.org/10.1007/s13365-020-00874-9DOI Listing
October 2020

Older Age is Associated with Higher Dolutegravir Exposure in Plasma and Cerebrospinal Fluid of People Living with HIV.

Clin Pharmacokinet 2021 01;60(1):103-109

Unit of Infectious Diseases, Department of Medical Sciences, University of Torino, c/o Amedeo Di Savoia Hospital, C.so Svizzera 164, 10149, Turin, Italy.

Background: People living with human immunodeficiency virus are ageing under combination antiretroviral treatments but data on drug exposure in serum and cerebrospinal fluid are limited. Dolutegravir is a widely used second-generation integrase strand transfer inhibitor: conflicting data suggest that neuropsychiatric side effects may present at a higher frequency in patients with higher dolutegravir serum concentrations.

Methods: We performed a retrospective analysis of our therapeutic drug monitoring registry identifying patients receiving once-daily dolutegravir without concomitant interacting drugs and significant clinical conditions. Data were analysed stratifying time after drug dose intake (maximum concentration 0.5-4 and trough concentration 21-27 h). Cerebrospinal fluid samples from patients enrolled in neurological studies and receiving dolutegravir were analysed for dolutegravir cerebrospinal fluid concentrations and cerebrospinal fluid-to-plasma ratios. Serum and cerebrospinal fluid concentrations were measured through validated chromatographic methods.

Results: We included 207 (providing 457 serum samples) and 41 patients (providing 41 cerebrospinal fluid samples). Participants were mostly male (68.2-72.8%) of median age of 50 years (50-53 years). Non-significant changes in dolutegravir maximum concentration and trough concentration were observed with age at Spearman's test (p values > 0.05); linear logistic regression showed a significant effect of age on dolutegravir trough concentration (p = 0.0013) (Fig. 1). Dolutegravir maximum concentration [3830 ng/mL (2311-5057) vs 4230 ng/mL (2919-5272), p = 0.311] and trough concentration [838 ng/mL (362-1587) vs 966 ng/mL (460-2085), p = 0.056] were non-significantly or borderline higher in patients aged > 50 years. Cerebrospinal dolutegravir concentrations were associated with plasma concentrations (ρ = 0.374, p = 0.016) and age (ρ = 0.537, p = 0.003); cerebrospinal fluid dolutegravir concentrations (13.8 vs 7.3 ng/mL, p = 0.015) and cerebrospinal fluid-to-plasma ratios (0.57 vs 0.32%, p = 0.017] were higher in participants aged > 50 years.

Conclusions: We observed an increase in dolutegravir exposure in serum and in cerebrospinal fluid in older patients living with human immunodeficiency virus.
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http://dx.doi.org/10.1007/s40262-020-00916-9DOI Listing
January 2021

Dual antiretroviral therapies are effective and safe regimens in the central nervous system of neurologically symptomatic people living with HIV.

AIDS 2020 11;34(13):1899-1906

Unit of Infectious Diseases, Department of Medical Sciences, University of Torino at Amedeo di Savoia Hospital, Torino.

Objective: Aim of this study was to compare cerebrospinal fluid (CSF) virological control, biomarkers and neurocognition of neurologically symptomatic patients on dual antiretroviral therapies (dual therapy) vs. 2 nucleoside reverse transcriptase inhibitors-based three-drug regimens (triple therapy).

Design: Retrospective monocentric cross-sectional study.

Methods: We analysed data from people living with HIV undergoing lumbar puncture for clinical/research reasons with plasma HIV-RNA less than 200 copies/ml and neurological/neurocognitive symptoms without significant contributing comorbidities. We measured CSF HIV-RNA, inflammation, blood-brain barrier integrity, neuronal damage and astrocytosis biomarkers (five biomarkers by ELISA and five indices by immunoturbidimetry) and recorded the neurocognitive performance (14 tests). CSF escape was defined as any case of CSF HIV-RNA 0.5 Log10 higher than viraemia or any case of detectable CSF HIV-RNA coupled with undetectable viraemia.

Results: A total of 78 patients on triple therapy and 19 on dual therapy were included. Overall, 75.3% male, median age 51 years (46-58), current CD4 count 545 cells/μl (349-735), time on current regimens 18 months (8-29), but length of plasma suppression 32 months (14-94). The two groups did not differ in terms of HIV-associated neurological diagnoses, demographic and viro-immunological features. Undetectable CSF HIV-RNA (73.7% in dual therapy vs. 78.2% in triple therapy, p.67) and CSF escape (21.1% in dual therapy vs. 19.2% in triple therapy, p.86) did not differ. No difference was observed in depression, anxiety, neurocognition (in 63 participants) nor in any tested biomarker.

Conclusion: In people living with HIV with neurological/neurocognitive symptoms, peripherally effective dual therapy can show CSF virosuppression, inflammation, neuronal and astrocyte integrity and neurocognition comparable to triple therapy.
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http://dx.doi.org/10.1097/QAD.0000000000002601DOI Listing
November 2020

Good times, bad times: A diary of a physician in the COVID-19 era.

Eur J Intern Med 2020 Jul 15;77:132-133. Epub 2020 May 15.

Infectious Diseases, Department of Medical Sciences, University of Turin, Turin, Italy.

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http://dx.doi.org/10.1016/j.ejim.2020.04.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7227561PMC
July 2020

Pilot prospective open, single-arm multicentre study on off-label use of tocilizumab in patients with severe COVID-19.

Clin Exp Rheumatol 2020 May-Jun;38(3):529-532. Epub 2020 May 1.

CMID, Centre of Research of Immunopathology and Rare Diseases, Coordinating Centre of the Network for Rare Diseases of Piemonte and Valle d'Aosta, ASL Città di Torino, Department of Clinical and Biological Sciences, University of Torino, and ASL Città di Torino, Italy.

Objectives: No agent has yet been proven to be effective for the treatment of patients with severe COVID-19.

Methods: We conducted a pilot prospective open, single-arm multicentre study on off-label use of tocilizumab (TCZ) involving 63 hospitalised adult patients (56 males, age 62.6±12.5) with severe COVID-19. Clinical and laboratory parameters were prospectively collected at baseline, day 1, 2, 7 and 14. No moderate-to-severe adverse events attributable to TCZ were recorded.

Results: We observed a significant improvement in the levels of ferritin, C-reactive protein, D-dimer. The ratio of the partial pressure of oxygen (Pa02) to the fraction of inspired oxygen (Fi02) improved (mean±SD Pa02/Fi02 at admission: 152±53; at day 7: 283.73±115.9, at day 14: 302.2±126, p<0.05). The overall mortality was 11%; D-dimer level at baseline, but not IL-6 levels were predictors of mortality. TCZ administration within 6 days from admission in the hospital was associated with an increased likelihood of survival (HR 2.2 95%CI 1.3-6.7, p<0.05).

Conclusions: In hospitalised adult patients with severe COVID-19, TCZ could be a safe option. An improvement in respiratory and laboratory parameters was observed. Future controlled trials in patients with severe illness are urgently needed to confirm the definite benefit with IL-6 target therapy.
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May 2020

96-week results of a dual therapy with darunavir/ritonavir plus rilpivirine once a day triple therapy in patients with suppressed viraemia: virological success and non-HIV related morbidity evaluation.

HIV Res Clin Pract 2020 02 4;21(1):34-43. Epub 2020 Mar 4.

Infectious Diseases Unit, DIBIC Luigi Sacco, University of Milan, Milan, Italy.

Antiretroviral therapies have been tested with the goal of maintaining virological suppression with a particular attention in limiting drug-related toxicity. With this aim we designed the DUAL study: a randomized, open-label, multicenter, 96 weeks-long pilot exploratory study in virologically suppressed HIV-1+ patients with the aim of evaluating the immunovirological success and the impact on non-HIV related morbidity of switching to a dual therapy with darunavir-ritonavir (DRV/r) and rilpivirine (RPV). We recruited patients who received a PI/r-containing HAART for ≥6 months, HIV-RNA < 50 cp/mL for ≥3 months, eGFR > 60 mL/min/1,73m2, without DRV or RPV RAMs. We randomized patients in arm A: RPV + DRV/r QD or arm B: ongoing triple therapy. The primary endpoint has been defined as the percentage of patients with HIV-RNA < 50 cp/mL at week 48 (ITT). VACS index, Framingham CVD risk (FRS) and urinary RBP (uRBP) were calculated. We used Chi-square or Fisher statistics for categorical variables and Mann-Whitney U for continuous ones. Forty-one patients were enrolled (22 in arm A, 14 in arm B, plus 5 screening failures): 30 patients reached 96 weeks: 100% had HIV-RNA < 50 cp/mL in arm A 91.7% in arm B. Similar changes were observed in median CD4/mL between baseline and week 96 (+59  - 31, p: n.s.). Thirty-one in arm A and 23 in arm B adverse events took place, whereas only 1 was serious (arm A: turbinate hypertrophy, unrelated to HAART). Among the 6 discontinuations (3 in A, 3 in B), only 1 was related to adverse event (arm A: G3 depression, insomnia, weakness). VACS index, median FRS and median uRBP values did not vary from baseline to week 96. At 96-weeks all patients switched to a QD 2-drug regimen based on DRV/r + RPV maintained HIV-RNA suppression, but a single patient who showed a virological failure at week 4. CD4 counts increased overtime without significant differences between the two arms. The novel dual regimen was well tolerated with the same amount of discontinuation as the control arm. VACS index, FRS and uRBP did not differ between arms at week 96.
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http://dx.doi.org/10.1080/25787489.2020.1734752DOI Listing
February 2020

Effectiveness of Switching to Darunavir/Cobicistat in Virologically Suppressed HIV-Positive Patients Receiving Ritonavir-Boosted Protease Inhibitor-Based Regimen: The "STORE" Study.

J Acquir Immune Defic Syndr 2020 07;84(3):290-294

Medical Affairs Department, Infectious Diseases, Janssen-Cilag SpA, Cologno Monzese, Italy; and.

Objective: This study investigates the effectiveness and tolerability of switching to a darunavir/cobicistat (DRV/c)-based antiretroviral regimen from a ritonavir-boosted protease inhibitor (PI/r)-based regimen in virologically suppressed HIV-positive patients. DRV trough values were also investigated.

Setting: Prospective, multicenter, single-country, noninterventional cohort study.

Methods: This study included patients on a PI/r-based ART for at least 12 months having plasma HIV-1 RNA <50 copies/mL since at least 6 months. The primary endpoint, defined as HIV-1 RNA <50 copies/mL, was measured at 48 ± 6 weeks from baseline. A secondary analysis was performed using the time to loss of virological response algorithm. Biochemical parameters, including DRV trough samples, were collected as per clinical practice and measured using high-performance liquid chromatography.

Results: Of 336 patients enrolled, 282 completed the study: 70.8% had plasma HIV-1 RNA <50 copies/mL at 48 weeks; using the time to loss of virological response algorithm, 82.7% maintained virological suppression. Virological failure was observed in 6 patients (1.8%). Adverse event-related discontinuations were 4.5%. After 48 weeks, we found a significant improvement in both triglycerides (median, 130 to 113.5 mg/dL, P = 0.0254) and high-density lipoprotein cholesterol (48 to 49 mg/dL, P < 0.0001) but no change in other biomarkers. DRV trough concentrations in 56 subjects showed a median value of 2862.5 (1469.5-4439) ng/mL, higher in women than in men (4221 vs. 2634 ng/mL, P = 0.046).

Conclusions: In stable HIV-1 positive virologically suppressed patients, the switch to DRV/c-based ART was beneficial in terms of low rates of virological failure and adverse events due to its high tolerability and improvement in triglycerides.
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http://dx.doi.org/10.1097/QAI.0000000000002331DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7289135PMC
July 2020

Safety and efficacy of daclatasvir at doses other than 60 mg daily in HIV/HCV co-infected subjects: Data from the ICONA/HepaICONA foundation cohorts.

Dig Liver Dis 2020 04 17;52(4):447-451. Epub 2020 Jan 17.

Clinic of Infectious Diseases, Health Sciences Department, University of Milan, Milan, Italy.

Background: Daclatasvir (DCV) is a HCV NS5A inhibitor whose plasma exposure may be influenced by co-administration with inducers or inhibitors of CYP3A4 such as many antiretrovirals.

Aims: Describe the use of different DCV dosages; assess if dose prescription complies with Summaries of Product Characteristics (SmPC); evaluate safety and efficacy of 60 versus 30/90 mg and adequate (i.e. concordant with SmPC) versus incorrect prescriptions.

Methods: Retrospective analysis of patients included in ICONA/HepaICONA starting a DCV-including treatment. Incidence rates of liver adverse events (LAE) were calculated; Poisson regression model was used to identify factors associated with LAE.

Results: 311 patients were included: 250 (80.4%) received DCV at a dosage of 60 mg, 52 (16.7%) 30 mg and 9 (2.9%) 90 mg. An inadequate dosage was used in 18 individuals (5.8%). No difference in SVR was observed (93.8% with 60 mg and 94.2% with 30/90 mg, p = 0.910; 93.5% with adequate and 100% with incorrect dosage, p = 0.277). There were 36 LAE with no differences in the two-paired groups. Decompensated liver disease was a risk factor for LAE (aRR = 2.37; p = 0.034), while HIV RNA < 50 copies/ml resulted protective (aRR = 0.22; p = 0.003).

Conclusions: DCV use resulted in high SVR rate regardless of dosage and correctness of prescription.
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http://dx.doi.org/10.1016/j.dld.2019.12.007DOI Listing
April 2020

Presence of Epstein-Barr virus DNA in cerebrospinal fluid is associated with greater HIV RNA and inflammation.

AIDS 2020 03;34(3):373-380

Unit of Infectious Diseases, Department of Medical Sciences, University of Torino.

Objective: The current study aimed to investigate whether cerebrospinal fluid (CSF) Epstein-Barr virus (EBV) or cytomegalovirus (CMV) DNA was associated with viral, inflammatory and neuronal damage biomarkers in people living with HIV (PLWH).

Design: A cross-sectional diagnostic study on CSF fluid samples in patients undergoing lumbar punctures for clinical reasons, to better understand the role of EBV and CMV in the CNS on HIV RNA replication, blood-brain-barrier (BBB) damage and biomarkers of neuronal damage/inflammation.

Methods: EBV, CMV DNA and HIV RNA were measured on CSF, through real time (RT)-PCR, from PLWHs undergoing lumbar punctures for clinical reasons (excluding oncho-haematological comorbidities). Immune-enzymatic assays evaluated blood-brain barrier inflammation and damage. Patients were stratified according to plasma HIV RNA levels in viremic (≥50 copies/ml) and aviremic (<50 copies/ml).

Results: We included 297 participants. Among 167 viremic patients CSF EBV and CMV DNA were detectable in 42 (25.1%) and 10 (6.3%) participants; among 130 aviremic individuals CSF EBV and CMV DNA were detectable in 12 (9.2%) and 0 (0%) participants, respectively. In viremic group detectable CSF EBV DNA was associated with CSF pleocytosis (P < 0.001), higher CSF HIV RNA (P < 0.001) and neopterin levels (P = 0.002). In aviremic participants detectable EBV DNA was associated with pleocytosis (P = 0.056), higher neopterin (P = 0.027) and immune globulins (P = 0.016) in the CSF; CSF escape was more common in those with detectable EBV DNA (50 vs. 21.2%, P = 0.036).

Conclusion: EBV DNA was frequently detected in the CSF of viremic and fewer aviremic patients on antiretroviral treatment. In PLWH without clinical evidence of encephalitis CSF EBV DNA was associated with higher biomarkers levels of neuronal damage/inflammation. The role of EBV reactivation in HIV-associated central nervous system disorders warrants further studies.
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http://dx.doi.org/10.1097/QAD.0000000000002442DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7773520PMC
March 2020

Population pharmacokinetics and pharmacogenetics of ritonavir-boosted darunavir in the presence of raltegravir or tenofovir disoproxil fumarate/emtricitabine in HIV-infected adults and the relationship with virological response: a sub-study of the NEAT001/ANRS143 randomized trial.

J Antimicrob Chemother 2020 03;75(3):628-639

Chelsea and Westminster NHS Trust, London, UK.

Objectives: NEAT001/ANRS143 demonstrated non-inferiority of once-daily darunavir/ritonavir (800/100 mg) + twice-daily raltegravir (400 mg) versus darunavir/ritonavir + tenofovir disoproxil fumarate/emtricitabine (245/200 mg once daily) in treatment-naive patients. We investigated the population pharmacokinetics of darunavir, ritonavir, tenofovir and emtricitabine and relationships with demographics, genetic polymorphisms and virological failure.

Methods: Non-linear mixed-effects models (NONMEM v. 7.3) were applied to determine pharmacokinetic parameters and assess demographic covariates and relationships with SNPs (SLCO3A1, SLCO1B1, NR1I2, NR1I3, CYP3A5*3, CYP3A4*22, ABCC2, ABCC10, ABCG2 and SCL47A1). The relationship between model-predicted darunavir AUC0-24 and C24 with time to virological failure was evaluated by Cox regression.

Results: Of 805 enrolled, 716, 720, 347 and 361 were included in the darunavir, ritonavir, tenofovir and emtricitabine models, respectively (11% female, 83% Caucasian). No significant effect of patient demographics or SNPs was observed for darunavir or tenofovir apparent oral clearance (CL/F); coadministration of raltegravir did not influence darunavir or ritonavir CL/F. Ritonavir CL/F decreased by 23% in NR1I2 63396C>T carriers and emtricitabine CL/F was linearly associated with creatinine clearance (P<0.001). No significant relationship was demonstrated between darunavir AUC0-24 or C24 and time to virological failure [HR (95% CI): 2.28 (0.53-9.80), P=0.269; and 1.82 (0.61-5.41), P=0.279, respectively].

Conclusions: Darunavir concentrations were unaltered in the presence of raltegravir and not associated with virological failure. Polymorphisms investigated had little impact on study-drug pharmacokinetics. Darunavir/ritonavir + raltegravir may be an appropriate option for patients experiencing NRTI-associated toxicity.
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http://dx.doi.org/10.1093/jac/dkz479DOI Listing
March 2020

Pharmacogenetic determinants of kidney-associated urinary and serum abnormalities in antiretroviral-treated HIV-positive patients.

Pharmacogenomics J 2020 04 16;20(2):202-212. Epub 2019 Oct 16.

Department of Medical Sciences, University of Turin, Amedeo di Savoia Hospital, Turin, Italy.

Tenofovir disoproxyl fumarate (TDF) has been associated with renal tubular abnormalities, phosphaturia and proteinuria (retinol binding protein, RBP, loss): vitamin D (VD) and PTH affect these markers. Aim was to understand if some single nucleotide polymorphisms (SNPs) were predictors of renal abnormalities in an Italian cohort of HIV-affected patients. DNA was analyzed through real-time PCR, urinary RBP corrected by creatinine (uRBP/Cr). The majority of patients received TDF. Abnormal uRBP/Cr was more frequent in TDF recipients: eGFR <90 mL/min and TDF were predictors in the whole cohort, whereas eGFR <90 mL/min, TDF concentrations and CYP24A1-3999TT in TDF-treated patients. Phosphate levels were higher low VD level patients: age <50 years, CYP27B1 + 2838CC genotype and non-European ancestry were predictors. PTH levels were border-line higher in TDF patients: non-European ancestry, females, TDF, VD levels < 30 ng/mL and SLC28A2-124CT/TT and ABCC2-24CC were predictors. For the first time, SNPs were associated with PTH, phosphate, calcium and tubular dysfunction in HIV-infected patients.
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http://dx.doi.org/10.1038/s41397-019-0109-xDOI Listing
April 2020

Switching from efavirenz to rilpivirine improves sleep quality and self-perceived cognition but has no impact on neurocognitive performances.

AIDS 2020 01;34(1):53-61

SC Malattie Infettive, Ospedale San Gerardo, Monza University of Milano-Bicocca Ospedale San Paolo, University of Milan, Milan Clinica di Malattie Infettive e Tropicali, ASST Spedali Civili, University of Brescia, Brescia Clinica di Malattie Infettive, Ospedale San Martino, Genoa Clinica di Malattie Infettive, University of Turin, Turin Clinica di Malattie Infettive, IRCCS Fondazione Ca' Granda Policinico di Milano, University of Milan, Milan, Italy.

Background: Efavirenz (EFV) association with neurocognitive impairment is debated. Whether switching away from EFV improves neurocognitive performances is still controversial.

Methods: In a randomized open-label controlled trial, patients under effective treatment with tenofovir disoproxil-fumarate (TDF), emtricitabine (FTC) and EFV, who had altered neurocognitive assessment (z-transformed score below -1 in at least one cognitive domain), depression, anxiety or low sleep-quality, were randomized 1 : 1 to immediate or delayed (24-weeks) switch to TDF/FTC/rilpivirine (RPV). Treatment efficacy, neurocognitive function, symptoms and quality of life were evaluated 12, 24 and 48 weeks after randomization.

Findings: Seventy-four patients were randomized to immediate (36 patients) or delayed switch (38 patients). At baseline, 63 and 25% of patients had z-scores below -1 in at least one or two neurocognitive domains, 31.1, 17.6 and 44.6% had significant depression or anxiety symptoms or low sleep quality. At week 24 (primary end-point), overall neurocognitive improvement was observed, with no statistically significant differences between arms, neither considering the global z score (between arms difference +0.1; P = 0.458), nor domain-specific z scores. Patients switching away from EFV had significant greater improvement of sleep quality index (between-arm difference -1.5; P = 0.011), self-reported cognitive failures (-6.2; P = 0.001) and CNS symptoms score (-5; P = 0.002), but not of anxiety or depression. No protocol defined virological failure, grade at least 3 lab abnormalities or drug-related serious adverse events were reported.

Conclusion: Our results do not support the hypothesis that switching to RPV improves cognitive function in patient under stable treatment with EFV. Nonetheless, improvements in neuropsychiatric symptoms, sleep quality and self-perceived cognition were observed.
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http://dx.doi.org/10.1097/QAD.0000000000002377DOI Listing
January 2020