Salvatore Nappa

Self-reported symptoms and medication side effects influence Adherence to highly active antiretroviral therapy in persons with HIV infection

Objectives: To identify variables predictive of nonadherence to highly active antiretroviral therapy (HAART) and to assess whether self‐reported symptoms or medication side effects are related to adherence. Design: Cross‐sectional multicenter study Adherence Italian Cohort Naive Antiretrovirals [AdICONA] within the Italian Cohort Naive Antiretrovirals (ICONA). Methods: Participants receiving HAART completed a 16‐item self‐administered questionnaire to assess nonadherence in the last 3 days as well as the type and intensity of 24 common HIV‐ and HAART‐related symptoms experienced during the last 4 weeks. Results: From May 1999 to March 2000, 358 persons were enrolled: 22% reported nonadherence and were less likely to have HIV RNA <500 copies/ml (odds ratio = 0.51; 95% confidence interval: 0.31‐0.85). Frequency of moderate/severe symptoms or medication side effects in nonadherent participants ranged from 3.6% to 30%. On univariate analysis, nausea, anxiety, confusion, vision problems, anorexia, insomnia, taste perversion, and abnormal fat distribution were significantly associated with nonadherence. Nonadherent persons had a higher mean overall symptom score (12.3 ± 9.2 versus 8.1 ± 6.6; p < .001) and mean medication side effect score (2.9 ± 2.7 versus 1.9 ± 1.9; p < .001) when compared with adherent participants. In the multivariate analysis, nausea (p = .003); anxiety (p = .006); younger age (p = .007); unemployment (p < .001); not recalling name, color, and timing of drugs (p = .009); running out of pills between visits (p = .002); and being too busy (p = .03) were independently associated with nonadherence in the last 3 days. Conclusions: In addition to patient characteristics, medication‐related variables, and reasons for nonadherence, patient‐reported symptoms and medication side effects were significantly associated with adherence to HAART.

Human immunodeficiency virus per se exerts atherogenic effects

OBJECTIVE Premature atherosclerosis in HIV-infected patients has been attributed to highly active antiretroviral therapy (HAART) and the associated metabolic complications. Whether HIV per se plays a role is an unresolved issue. The purpose of this study was to evaluate whether HIV per se exerts atherogenic effects. METHODS We measured carotid intima-media thickness (IMT) and brachial endothelial-dependent (FMD) and endothelial-independent (NMD) vasodilation in 38 naïve untreated HIV-infected patients and 41 healthy control subjects. RESULTS Control subjects were selected as to match the HIV patients for metabolic risk factors. Mean carotid IMT was higher in HIV patients (0.85+/-0.2mm; p<0.001) than in controls (0.63+/-0.1mm). In a stepwise multiple regression model, the changes in carotid IMT were predicted by the duration of HIV infection (p<0.001) and CD4 T-cells (p=0.035). Brachial FMD was impaired in HIV patients (8.8+/-3% versus 12.2+/-3% in controls; p<0.001). In contrast, NMD values practically overlapped in the HIV patients and controls. Analysis of the data in relation to viral load showed that FMD was significantly more impaired in the subgroup of patients with viral load values above the median (p<0.001). In addition, there was a highly significant, inverse correlation between FMD and the HIV-RNA copies (p<0.001). CONCLUSION HIV infection causes functional and structural vascular alterations in a very early stage of the infection independent of HAART and metabolic factors. The data lend support to the viral infectious theory of atherosclerosis. Early assessment of the vascular status in HIV-infected patients is suggested.

Cognitive and affective disorders associated to HIV infection in the HAART era: findings from the NeuroICONA study

Objective: To assess the natural story of HIV‐associated affective and cognitive disorders and the relationship with clinical, pharmacological, immunological and behavioural factors.

Tenofovir Disoproxil Fumarate in the Clinical Practice: An Overview

Tenofovir disoproxil fumarate (tenofovir DF) is the generic name of the chemical compound 9[R(2[[bis]]isopropoxycarbonyl) oxy]methoxy]phosphonyl]methoxy]propyl] adenine fumarate (1:1), the prodrug of tenofovir, the first nucleotide analogue reverse transcriptase inhibitor approved in October 2001 by the Food and Drugs Administration in USA and then, in February 2002, by the European Medicines Evaluation Agency in Europe for the treatment of

Management of multidrug-resistant Pseudomonas aeruginosa in the intensive care unit: state of the art

ABSTRACT Introduction: Pseudomonas aeruginosa (PA) is one of the most important causes of healthcare-related infections among Gram-negative bacteria. The best therapeutic approach is controversial, especially for multidrug-resistant (MDR) and extensively drug-resistant (XDR) strains as well as in the setting of most severe patients, such as in the intensive care unit (ICU). Areas covered: This article addresses several points. First, the main microbiological aspects of PA, focusing on its wide array of resistance mechanisms. Second, risk factors and the worse outcome linked to MDR-PA infection. Third, the pharmacological peculiarity of ICU patients, that makes the choice of a proper antimicrobial therapy difficult. Eventually, the current therapeutic options against MDR-PA are reviewed, taking into account the main variables that drive antimicrobial optimization in critically ill patients. Literature search was carried out using Pubmed and Web of Science. Expert commentary: Methodologically rigorous studies are urgently needed to clarify crucial aspects of the treatment against MDR-PA, namely monotherapy versus combination therapy in empiric and targeted settings. In the meanwhile, useful options are represented by newly approved drugs, such as ceftolozane/tazobactam and ceftazidime/avibactam. In critically ill patients, at least as empirical approach, a combination therapy is a prudent choice when a MDR-PA strain is suspected.

Response to: 'Letter to the Editor: "Management of multidrug-resistant Pseudomonas aeruginosa in the Intensive Care Unit: state of the art"'

Dear Editor, We truly thank Dr Plant and colleagues for taking an interest in our review, raising an important issue about the risk of resistance development and clinical failure when ceftolozane/tazobactam (TOL/TAZ) is used against multidrug-resistant (MDR) Pseudomonas aeruginosa (PA) [1,2]. TOL/TAZ belongs to the new wave of beta-lactam /beta-lactamase inhibitor combinations and bases its efficacy against Gram-negative bacteria on ceftolozane’s higher stability versus AmpC β-lactamase than the predecessor beta-lactam companions of tazobactam [3]. The combination with the beta-lactamase inhibitor allows TOL to target many Enterobacteriaceae producing extendedspectrum beta-lactamases [4]. Nevertheless, the most intriguing feature of TOL is its potent in vitro activity against PA, not impaired by the most important resistance mechanisms toward beta-lactams such as AmpC-type beta-lactamases, decrement of outer membrane permeability through loss of porins and up-regulation of efflux pumps [5]. There is a huge amount of data across the world confirming the potent activity of TOL/TAL against clinical isolates of PA, including MDR and even extensively-drug resistant (XDR) strains. For example, a large Italian multicenter study, conducted from September 2013 to November 2014, showed that TOL/TAZ was the most active antibiotic against PA [6]. The authors collected 935 PA strains (related to pneumonia or bloodstream infections), of which 37.2% expressed an MDR phenotype: overall, TOL/TAZ turned out to be activity against 90.9% of PA isolates, followed by amikacin (88.0% susceptibility) [6]. In a larger series from the United States, 3,851 clinical isolates of PA (15.8% classified as MDR, 9.4% as XDR) were collected from 2012 to 2015 [7]. TOL/TAZ was the most active against 97.0% of cases among the antibiotics tested, namely, meropenem, amikacin, piperacillin/tazobactam, colistin, cefepime, and ceftazidime [7]. Of note, TOL/TAZ showed highest activity among beta-lactams against MDR (84.0%) and XDR (76.9%) strains [7]. This pattern (superiority of TOL/TAZ over other antipseudomonal beta-lactams) has been also observed in studies from other parts of the world. For instance, a recent report from Australia and New Zealand on 449 clinical isolates (mainly related to bloodstream infections and pneumonia from 2013 and 2105) demonstrated that TOL/TAZ retained good activity against PA strains resistant to ceftazidime, piperacillin/tazobactam, meropenem [8]. Similar results emerged from another report related to four Latin American countries (Argentina, Brazil, Mexico, Chile) over a 3-year period (2013–2015) in which 537 PA isolates were collected: TOL/ TAZ inhibited 86.8% of the strains, being the most active betalactam agent [9]. On this basis, it does not come as a surprise the scientific attention given to TOL/TAZ as an important drug able to fruitfully enrich the therapeutic armamentarium against PA, especially MDR and XDR strains. A relevant issue is to better define its place in therapy: currently, TOL/TAZ has been approved only for complicated urinary tract infections, including pyelonephritis, and for complicated intra-abdominal infections [3]. Differently, physicians need to resort to off-label prescribing, as was the case described by Dr Plant and colleagues [1]. They authors describe the in vivo development of TOL/TAZ resistance in a patient suffering from nosocomial pneumonia caused by an MDR-PA strain (carbapenem-resistant), treated with TOL/TAZ at the following dosage: 1.5 g three times a day [1]. They make a plea not to underestimate the risk of resistance occurrence and clinical failure when using TOL/TAZ against PA. Of course, their appeal is sensible and it overlaps with similar reflections made by other authoritative authors, who have advised caution in the use of novel antibiotics such as TOL/TAZ, since a widespread utilization would likely result in an increase of resistance, as it occurs in most other antimicrobials, thereby leading to the loss of efficacy of a potent weapon [10]. So, the crucial question is the accurate selection of patients who deserve treatment with TOL/TAZ, both empiric and targeted, in order to achieve the best outcome for the patient. In the case described by Dr Plant and colleagues the choice of TOL/TAZ appears appropriate in the light of the resistance profile showed by the PA strain [1]. As matter of fact, being that PA is a remarkable cause of nosocomial pneumonia, TOL/ TAZ, although through off-label prescribing, has been already used for respiratory tract infections [2] prompting a randomized clinical trial (ClinicalTrials.gov identifier: NCT02070757).

Current and emerging pharmacotherapy for the treatment of bacterial peritonitis

ABSTRACT Introduction: Spontaneous bacterial peritonitis (SBP) is the quintessential model of bacterial infection in cirrhotic patients. In these particularly frail subjects, infections clearly worsen prognosis increasing substantially mortality. Furthermore, treatment of SBP has become more challenging because of the growing impact of multidrug-resistant (MDR) bacteria. Areas covered: This review addresses the reasons behind the change in therapeutic recommendations for SBP that have occurred in the past few years, by focusing on the following aspects: the importance of an early appropriate empirical treatment, the difference between nosocomial and non-nosocomial forms and the overall microbiological shift (rise of Gram-positive bacteria and MDR strains) that have affected SBP. Expert opinion: Until recently, third-generation cephalosporins have represented the cornerstone of SBP treatment, a safe choice covering the most important causative agents, namely Enterobacteriaceae. Unfortunately, massive exposure to health systems makes cirrhotic patients prone to MDR infections, which poses significant challenges, all the while not forgetting to strike a balance between effective antimicrobial activity and the risk of toxicity in these fragile subjects. Moreover, there is sparse information about new antibiotics in cirrhotic patients and about drugs levels in ascitic fluid. Therefore, further research is needed to optimize the treatment of SBP.

NS5B polymerase inhibitors in phase II clinical trials for HCV infection

ABSTRACT Introduction: Hepatitis C virus (HCV) infection might be the first chronic viral disease to be eradicated without the introduction of a prophylactic vaccine. This is essentially due to therapeutic revolution encapsulated by the advent of direct-acting antivirals (DAA) agents, whose efficacy, safety and tolerability (all oral regimens) have made the previous standard of care (interferon plus ribavirin) a vestige of the past. The new regimens achieve very high response rates and have an excellent tolerability profile. Notwithstanding, the first wave of DAAs has brought over problems regarding costs and failures which warrant research and development of further antiviral molecules. Areas covered: This review outlines the main clinical data concerning novel NS5B polymerase inhibitors currently in pipeline, focusing on the ones that have completed a phase 2 trial. Expert opinion: NS5B is one the main viral target for anti-HCV therapy. The large majority of the approved regimens so far include a NS5B inhibitor. Although not frequently, failure related to mutations can occur. The potential place in therapy in the mid-term of new NS5B inhibitors may be, in the first instance, the role of backbone in salvage combinations with DAAs of other classes.

Morphological and functional abnormalities in platelets exposed in vitro to ioglicinic acid, a new ionic contrast medium.

SummaryThe inhibitory effect on platelet function induced by several radiographic contrast media is still poorly understood. In this study platelet abnormalities caused byin vitro addition of ioglicinic acid, a new ionic contrast medium, were evaluated. The appearance of several granules similar to dense bodies associated with shape change and internal reorganization were detected by electron microscopy techniques. A functional study revealed a marked decrease in the aggregating response of platelets to adenosine diphosphate and calcium ionophore A23187, while aggregation in response to collagen was completely normal. It is suggested that ioglicinic acid induces platelet abnormalities related to the effect on calcium movements and that studies with this contrast medium may help the understanding of some basic events of platelet activation.