National Institute for Infectious Diseases Lazzaro Spallanzani IRCCS
National Institute for Infectious Diseases Lazzaro Spallanzani IRCCS
Mills A.,Anthony Mills MD Inc. |
Antinori A.,National Institute for Infectious Diseases Lazzaro Spallanzani IRCCS |
Clotet B.,University of Barcelona |
Fourie J.,Dr urie Medical Center |
And 5 more authors.
HIV Medicine | Year: 2013
Objectives: The aim of the study was to compare the neuropsychiatric safety and tolerability of rilpivirine (TMC278) vs. efavirenz in a preplanned pooled analysis of data from the ECHO and THRIVE studies which compared the safety and efficacy of the two drugs in HIV-1 infected treatment naïve adults. Methods: ECHO and THRIVE were randomized, double-blind, double-dummy, 96-week, international, phase 3 trials comparing the efficacy, safety and tolerability of rilpivirine 25mg vs. efavirenz 600mg once daily in combination with two background nucleoside/tide reverse transcriptase inhibitors. Safety and tolerability analyses were conducted when all patients had received at least 48 weeks of treatment or discontinued earlier. Differences between treatments in the incidence of neurological and psychiatric adverse events (AEs) of interest were assessed in preplanned statistical analyses using Fisher's exact test. Results: At the time of the week 48 analysis, the cumulative incidences in the rilpivirine vs. efavirenz groups of any grade 2-4 treatment-related AEs and of discontinuation because of AEs were 16% vs. 31% (P<0.0001) and 3% vs. 8% (P=0.0005), respectively. The incidence of treatment-related neuropsychiatric AEs was 27% vs. 48%, respectively (P<0.0001). The incidence of treatment-related neurological AEs of interest was 17% vs. 38% (P<0.0001), and that of treatment-related psychiatric AEs of interest was 15% vs. 23% (P=0.0002). Dizziness and abnormal dreams/nightmares occurred significantly less frequently with rilpivirine vs. efavirenz (P<0.01). In both groups, patients with prior neuropsychiatric history tended to report more neuropsychiatric AEs but rates remained lower for rilpivirine than for efavirenz. Conclusions: Rilpivirine was associated with fewer neurological and psychiatric AEs of interest than efavirenz over 48 weeks in treatment-naïve, HIV-1-infected adults. © 2013 British HIV Association.
Bordoni V.,National Institute For Infectious Diseases Lazzaro Spallanzani Irccs
Journal of acquired immune deficiency syndromes (1999) | Year: 2013
HIV infection affects dendritic cells (DCs) number, maturation, and function although the cause remains largely unknown. Purified CD34+ hematopoietic progenitor cells (HPCs) obtained from bone marrow of chronic HIV-infected patients were investigated for the differentiative capability toward mature DCs. HIV, although not in active replication, was found able to impair CD34+ HPC differentiation into mature DCs. These results suggest that DCs impairment found in HIV-infected patients may be related to a failure by bone marrow CD34 HPCs to produce an adequate number of DCs.
Tempestilli M.,National Institute for Infectious Diseases Lazzaro Spallanzani IRCCS |
Gentilotti E.,National Institute for Infectious Diseases Lazzaro Spallanzani IRCCS |
Tommasi C.,National Institute for Infectious Diseases Lazzaro Spallanzani IRCCS |
Nicastri E.,National Institute for Infectious Diseases Lazzaro Spallanzani IRCCS |
And 4 more authors.
International Immunopharmacology | Year: 2013
It has been shown that P-glycoprotein (P-gp) can greatly affect the cell uptake of antiretroviral drugs, thus hampering their access to HIV-1 replication sites. Lymphocytes are important sites of replication of HIV and target of other drugs, modification on these cells of P-gp could have an effect on pharmacokinetic of antiretrovirals and drug substrates. Blood samples from 16 healthy volunteers were used to determine the expression of P-gp on total, T and T helper lymphocytes after exposure to darunavir, a second generation protease inhibitor, and raltegravir, the first approved integrase inhibitor. Moreover, the effect of the drugs on P-gp functional activity was also studied by the rhodamine-123 efflux test. Darunavir, but not raltegravir, exposure caused a moderate, dose-dependent increment in P-gp expression in total, T and T helper lymphocytes, as demonstrated by the relative frequency of P-gp + cells and by the amount of P-gp molecules present on cell surface. Functionally, incubation with darunavir led to a marked inhibition of P-gp activity measured by the efflux of rhodamine-123 similar to that observed by verapamil, a specific P-gp inhibitor. Raltegravir was not able to modify the efflux of rhodamine-123 level. Data show that darunavir, unlike raltegravir, may modify the expression and functionality of P-gp on human lymphocytes, thus leading to potential changes in intracellular concentrations of darunavir in patients treated with other drugs substrate of P-gp and vice versa. Our study highlights the need for studies on drug interactions via the P-gp modulation mechanism, especially with the current multi-drug regimens. © 2013 Elsevier B.V.
Agrati C.,National Institute for Infectious Diseases Lazzaro Spallanzani |
D'Offizi G.,National Institute for Infectious Diseases Lazzaro Spallanzani IRCCS |
Gougeon M.-L.,Institute Pasteur Paris |
Malkovsky M.,University of Wisconsin - Madison |
And 5 more authors.
AIDS Reviews | Year: 2011
Despite a long-lasting global effort, the Holy Grail quest for a protective vaccine, able to confer prevention to HIV infection, did not reach the hoped for results, nor seems able to do so in the near future. Since mucosal surfaces of the host serve as the main entry point for HIV, it seems now logical to switch from a systemic to a localized view of events, in order to reveal critical steps useful in designing new and different vaccination strategies. In this context, the recent description of the very early phases of infection, from the eclipse to the viremia peak phase, seems to define a point-of-no-return threshold after which the main HIV infection steps, i.e. the massive destruction of the CD4+CCR5+ cell pool, the destruction of the mucosal physical barrier, and the establishment of reservoir sanctuaries, have already been accomplished. Nevertheless, the underlying mechanisms, the timing, and the consequences of evasion mechanisms exploited by HIV are still under scrutiny. Innate immunity, as part of a rapid lymphoid stress surveillance system, is known to play a central role in host responses to many infectious agents. In particular, V©9V™2 T-cells are able to quickly respond to danger signals without the need for classical major histocompatibility complex presentation, and may act as a bridge between innate and acquired arms of immune response, being able to kill infected/transformed cells, release antimicrobial soluble factors, and increase the deployment of other innate and acquired responses. Many experimental evidences suggest a direct role of circulating V©9V™2 T-cells during HIV disease. They may exert a direct anti-HIV role by secreting chemokines competing for HIV entry coreceptors as well as other soluble antiviral factors, and by killing infected cells by cytotoxic natural killer-like mechanisms. Moreover, they were found progressively depleted and anergic in advanced stages of HIV disease, this effect being directly linked to uncontrolled HIV replication. Scarce evidences are available on the involvement of mucosal gamma/delta T-cells during the early phases of HIV infection. In particular, the relative cause/effect links between HIV infection, destruction of the mucosal physical barrier, nonspecific activation of the immune system, and mucosal innate cell activation and effector functions, are still not completely defined. In order to attain an effective manipulation of innate immune cells, aiming at the induction of an effective adaptive immunity against HIV, any information on the role of mucosal antiviral factors and innate immune cells will be very important. The aim of this review is to summarize the information onthe role of gamma/delta T-cells during HIV infection, from the general circulating population to mucosal sites, in order to better describe areas deserving increased attention. In particular, strategies enhancing gamma/delta T-cell functions may open the possibility to formulate new immunotherapeutic regimens, which could impact the improvement of immune control of HIV disease. © Permanyer Publications 2011.
Van Lunzen J.,University of Hamburg |
Van Lunzen J.,ViiV Healthcare |
Pozniak A.,Chelsea and Westminster NHS Foundation Trust Hospital |
Gatell J.M.,University of Barcelona |
And 8 more authors.
Journal of Acquired Immune Deficiency Syndromes | Year: 2016
This open-label, multinational, pilot study randomized (1:2 ratio) adults with HIV-1 RNA <40 copies per milliliter and nucleos(t)ide-related safety/tolerability issues to switch to ritonavir-boosted atazanavir (ATV/r) plus tenofovir disoproxil fumarate/emtricitabine (n = 37) or the nucleos(t)ide reverse transcriptase inhibitor-sparing regimen of ATV/r plus raltegravir (RAL) (n = 72). At 24 weeks, 35/37 (94.6%) and 58/72 (80.6%) of patients, respectively, maintained virological suppression, the primary endpoint, and 1 (2.7%) and 7 (9.7%), respectively, experienced virological rebound. Corresponding 48-week proportions were 86.5%, 69.4%, 2.7%, and 12.5%, respectively. Adherence was lower and treatment discontinuation was higher with ATV/r+RAL. In conclusion, switching to ATV/r+RAL resulted in a higher virological rebound rate than switching to ATV/r plus tenofovir disoproxil fumarate/emtricitabine. Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Puro V.,National Institute for Infectious Diseases Lazzaro Spallanzani IRCCS |
Palummieri A.,National Institute for Infectious Diseases Lazzaro Spallanzani IRCCS |
De Carli G.,National Institute for Infectious Diseases Lazzaro Spallanzani IRCCS |
Piselli P.,National Institute for Infectious Diseases Lazzaro Spallanzani IRCCS |
Ippolito G.,National Institute for Infectious Diseases Lazzaro Spallanzani IRCCS
BMC Infectious Diseases | Year: 2013
Background: To investigate perceptions and attitude to prescribe Pre-Exposure Prophylaxis (PrEP) among HIV specialists.Methods: A questionnaire developed through a Focus Group and literature review was administered to a convenience sample of HIV specialists during educational courses in two Regions and an online survey in February-May 2012. Participants were classified as having a positive or negative attitude according to their willingness to prescribe PrEP. Demographic and working information, experience with HIV-infected patients, information and provision of antiretrovirals to uninfected persons, self-reported knowledge, perceptions and concerns regarding PrEP were assessed. The association between a different attitude towards PrEP prescription and selected characteristics was assessed through univariate and multivariate regression analysis.Results: Of 311 specialists, 70% would prescribe PrEP, mainly to serodiscordant partners (64%) but also to people at ongoing, high risk of HIV infection (56%); 66% advocated public support of costs. A negative attitude towards PrEP was significantly associated with lack of provision of information on, and prescription of, antiretroviral post-exposure prophylaxis; specialists with a negative attitude believed behavioural interventions to be more effective than PrEP and were more concerned about toxicity. Overall, 90% of specialists disagreed regarding a lack of time for engaging in prevention counselling and PrEP monitoring; 79% would welcome formal guidelines, while those with a negative attitude did not consider this advisable.Conclusions: Although conflicting attitudes appear evident, most specialists seem to be willing, with guidance from normative bodies, to promote PrEP within multiple prevention strategies among vulnerable populations. More scientific evidence regarding effectiveness could overcome resistance. © 2013 Puro et al.; licensee BioMed Central Ltd.
Raffi F.,University of Nantes |
Babiker A.G.,University College London |
Richert L.,French Institute of Health and Medical Research |
Molina J.-M.,University Paris Diderot |
And 15 more authors.
The Lancet | Year: 2014
Background Standard first-line antiretroviral therapy for HIV-1 infection includes two nucleoside or nucleotide reverse transcriptase inhibitors (NtRTIs), but these drugs have limitations. We assessed the 96 week efficacy and safety of an NtRTI-sparing regimen. Methods Between August, 2010, and September, 2011, we enrolled treatment-naive adults into this randomised, open-label, non-inferiority trial in treatment-naive adults in 15 European countries. The composite primary outcome was change to randomised treatment before week 32 because of insufficient virological response, no virological response by week 32, HIV-1 RNA concentration 50 copies per mL or higher at any time after week 32; death from any cause; any new or recurrent AIDS event; or any serious non-AIDS event. Patients were randomised in a 1:1 ratio to receive oral treatment with 400 mg raltegravir twice daily plus 800 mg darunavir and 100 mg ritonavir once daily (NtRTI-sparing regimen) or tenofovir-emtricitabine in a 245 mg and 200 mg fixed-dose combination once daily, plus 800 mg darunavir and 100 mg ritonavir once daily (standard regimen). This trial was registered with ClinicalTrials.gov, number NCT01066962. Findings Of 805 patients enrolled, 401 received the NtRTI-sparing regimen and 404 the standard regimen, with median follow-up of 123 weeks (IQR 112-133). Treatment failure was seen in 77 (19%) in the NtRTI-sparing group and 61 (15%) in the standard group. Kaplan-Meier estimated proportions of treatment failure by week 96 were 17·8% and 13·8%, respectively (difference 4·0%, 95% CI -0·8 to 8·8). The frequency of serious or treatment-modifying adverse events were similar (10·2 vs 8·3 per 100 person-years and 3·9 vs 4·2 per 100 person-years, respectively). Interpretation Our NtRTI-sparing regimen was non-inferior to standard treatment and represents a treatment option for patients with CD4 cell counts higher than 200 cells per μL. Funding European Union Sixth Framework Programme, Inserm-ANRS, Gilead Sciences, Janssen Pharmaceuticals, Merck Laboratories. © 2014 Elsevier Ltd.
PubMed | Azienda Ospedaliera Lecco, Santissima Annunziata Hospital, National Institute for Infectious Diseases Lazzaro Spallanzani IRCCS, University of Bari and 6 more.
Type: Journal Article | Journal: Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases | Year: 2016
Migrant and Italian HIV-infected patients (n = 5773) enrolled in the ICONA cohort in 2004-2014 were compared for disparities in access to an initial antiretroviral regimen and/or risk of virologic failure (VF), and determinants of failure were evaluated. Variables associated with initiating antiretroviral therapy (ART) were analysed. Primary endpoint was time to failure after at least 6 months of ART and was defined as: VF, first of two consecutive virus loads (VL) >200 copies/mL; treatment discontinuation (TD) for any reason; and treatment failure as confirmed VL >200 copies/mL or TD. A Poisson multivariable analysis was performed to control for confounders. Migrants presented significantly lower CD4 counts and more frequent AIDS events at baseline. When adjusting for baseline confounders, migrants presented a lower likelihood to begin ART (odds ratio 0.80, 95% confidence interval (CI) 0.67-0.95, p 0.012). After initiating ART, the incidence VF rate was 6.4 per 100 person-years (95% CI 4.8-8.5) in migrants and 2.7 in natives (95% CI 2.2-3.3). Multivariable analysis confirmed that migrants had a higher risk of VF (incidence rate ratio 1.90, 95% CI 1.25-2.91, p 0.003) and treatment failure (incidence rate ratio 1.16, 95% CI 1.01-1.33, p 0.031), with no differences for TD. Among migrants, variables associated with VF were age, unemployment and use of a boosted protease inhibitor-based regimen versus nonnucleoside reverse transcriptase inhibitors. Despite the use of more potent and safer drugs in the last 10 years, and even in a universal health care setting, migrants living with HIV still present barriers to initiating ART and an increased risk of VF compared to natives.
PubMed | Institute of Molecular Virology and Cell Biology, National Institute for Infectious Diseases Lazzaro Spallanzani IRCCS, University College London and Laval University
Type: Journal Article | Journal: PLoS pathogens | Year: 2017
An unprecedented Ebola virus (EBOV) epidemic occurred in 2013-2016 in West Africa. Over this time the epidemic exponentially grew and moved to Europe and North America, with several imported cases and many Health Care Workers (HCW) infected. Better understanding of EBOV infection patterns in different body compartments is mandatory to develop new countermeasures, as well as to fully comprehend the pathways of human-to-human transmission. We have longitudinally explored the persistence of EBOV-specific negative sense genomic RNA (neg-RNA) and the presence of positive sense RNA (pos-RNA), including both replication intermediate (antigenomic-RNA) and messenger RNA (mRNA) molecules, in the upper and lower respiratory tract, as compared to plasma, in a HCW infected with EBOV in Sierra Leone, who was hospitalized in the high isolation facility of the National Institute for Infectious Diseases Lazzaro Spallanzani (INMI), Rome, Italy. We observed persistence of pos-RNA and neg-RNAs in longitudinally collected specimens of the lower respiratory tract, even after viral clearance from plasma, suggesting possible local replication. The purpose of the present study is to enhance the knowledge on the biological features of EBOV that can contribute to the human-to-human transmissibility and to develop effective intervention strategies. However, further investigation is needed in order to better understand the clinical meaning of viral replication and shedding in the respiratory tract.
PubMed | University of Pisa, University of Oxford and National Institute for Infectious Diseases Lazzaro Spallanzani IRCCS
Type: Review | Journal: Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases | Year: 2016
Hepatitis C virus (HCV) is a major global health burden accounting for around 170 million chronic infections worldwide. Since its discovery, which dates back to about 30years ago, many details of the viral genome organization and the astonishing genetic diversity have been unveiled but, owing to the difficulty of culturing HCV invitro and obtaining fully susceptible yet immunocompetent invivo models, we are still a long way from the full comprehension of viral life cycle, host cell pathways facilitating or counteracting infection, pathogenetic mechanisms invivo, and host defences. Here, we illustrate the viral life cycle into cells, describe the interplay between immune and genetic host factors shaping the course of infection, and provide details of the molecular approaches currently used to genotype, monitor replication invivo, and study the emergence of drug-resistant viral variants.