Massimiliano Lanzafame | University of Trento (original) (raw)

Papers by Massimiliano Lanzafame

Journal of Cardiovascular Medicine, Dec 1, 2018

Aims A global outbreak of Mycobacterium chimaera infections following cardiac surgery and linked ... more Aims A global outbreak of Mycobacterium chimaera infections following cardiac surgery and linked to contaminated heater-cooler units (HCUs) is currently ongoing. Neither the status of this outbreak in Italy nor the mitigation strategies adopted by adult cardiac surgery units (ACSUs) are currently known. In 2017, the Italian Society of Cardiac Surgery launched a national survey among the Italian ACSU to shed some light on this issue. Methods In Italy, there are 90 ACSUs across 20 regions. From May to November 2017, these ACSUs were surveyed collecting data on patients diagnosed with MC infections, ACSU workload, HCU models in use and control measures adopted in the operatory room. Results The response rate was 87.8%. The median number of cardiac procedures at each ACSU was 450/year [interquartile range (IQR) 350-650 procedures/year], and nationally, the number of procedures/year exceeded 40k. In Italy, seven patients with M. chimaera infections following cardiac procedures have been reported since 2015: all had aortic or valvular surgery as the first procedure; the median latency between the first operation and the infection was 2 years (IQR 2-3.25). Mortality for patients requiring redo cardiac surgery was 50%. M. chimaera infections risk was 0.4-1 patient every 1000 cardiac procedures. The most common HCU model in Italy is the 3T HCU (70.9%). The most common control measures adopted included implementing new HCU disinfection protocols, using sterile or filtrated water in the HCU and displacing HCU fans away from the patient: HCU replacement and microbiology testing were instead infrequent. Conclusion In Italy, the risk of contracting M. chimaera infections and the mortality reported are in line with other European countries, but significant heterogeneity exists on the mitigation strategies adopted to prevent further M. chimaera inoculations, suggesting the development of national guidelines.

Journal of symptoms and signs, Jan 19, 2015

Ritonavir was one of the four potent synthetic protease inhibitors (PI), approved by FDA between ... more Ritonavir was one of the four potent synthetic protease inhibitors (PI), approved by FDA between 1995 and 1997 that revolutionised HIV therapy. Boosted protease inhibitor regimens combine ritonavir with a second protease inhibitor to enhance patient exposure to the latter agent, preventing or overcoming resistance and allowing less frequent dosing, potentially improving adherence. The advantages offered by ritonavir boosting are primarily attributable to the drug’s pharmacokinetics properties. Ritonavir inhibition’s of the cytochrome P-450 CYP3A4 enzyme reduces the metabolism of concomitantly administered PI and changes minimum concentration and half-life. As a result, the bioavailability of the boosted PI is increased and improved penetration into HIV reservoirs may be achieved. Moreover, at low dose ritonavir boosts the second inhibitor without contributing significantly to the side effect profile of the regimen. The very recent finding that ritonavir, despite administered at a low dose, can reach intracellular levels sufficient to exert an antiviral activity itself, suggests several hypothetic issues for its use in clinical practice and further in vitro and in vivo studies, before definitely switching therapy to other booster molecules. Keywords: ritonavir; boosted protease inhibitor; pharmacokinetics properties; cytochrome P450. Received: June 5, 2014; Accepted: October 21, 2014; Published: January 19, 2015 Corresponding Author: Massimiliano Lanzafame, Via Strada Romana 11, San Bonifacio 37047 (Verona), Italy. E-mail: lanzafame.massimiliano@gmail.com .

Frontiers in Neurology, Sep 21, 2018

AIDS dementia complex (ADC) and HIV-associated neurocognitive disorders (HAND) are complications ... more AIDS dementia complex (ADC) and HIV-associated neurocognitive disorders (HAND) are complications of HIV-1 infection. Viral infections are risk factors for the development of neurodegenerative disorders. Aging is associated with low-grade inflammation in the brain, i.e., the inflammaging. The molecular mechanisms linking immunosenescence, inflammaging and the pathogenesis of neurodegenerative disorders, such as Alzheimer's disease (AD) and Parkinson's disease, are largely unknown. ADC and HAND share some pathological features with AD and may offer some hints on the relationship between viral infections, neuroinflammation, and neurodegeneration. β 2-microglobulin (β 2 m) is an important pro-aging factor that interferes with neurogenesis and worsens cognitive functions. Several studies published in the 80-90s reported high levels of β 2 m in the cerebrospinal fluid of patients with ADC. High levels of β 2 m have also been detected in AD. Inflammatory diseases in elderly people are associated with polymorphisms of the MHC-I locus encoding HLA molecules that, by associating with β 2 m, contribute to cellular immunity. We recently reported that HLA-C, no longer associated with β 2 m, is incorporated into HIV-1 virions, determining an increase in viral infectivity. We also documented the presence of HLA-C variants more or less stably linked to β 2 m. These observations led us to hypothesize that some variants of HLA-C, in the presence of viral infections, could determine a greater release and accumulation of β 2 m, which in turn, may be involved in triggering and/or sustaining neuroinflammation. ADC is the most severe form of HAND. To explore the role of HLA-C in ADC pathogenesis, we analyzed the frequency of HLA-C variants with unstable binding to β 2 m in a group of patients with ADC. We found a higher frequency of unstable HLA-C alleles in ADC patients, and none of them was harboring stable HLA-C alleles in homozygosis. Our data suggest that the role of HLA-C variants in ADC/HAND pathogenesis deserves further studies. If Zipeto et al. HIV-1-Associated Neurocognitive Disorders confirmed in a larger number of samples, this finding may have practical implication for a personalized medicine approach and for developing new therapies to prevent HAND. The exploration of HLA-C variants as risk factors for AD and other neurodegenerative disorders may be a promising field of study.

Abnormal expansion or depletion of particular lymphocyte subsets is associated with clinical mani... more Abnormal expansion or depletion of particular lymphocyte subsets is associated with clinical manifestations such as HIV progression to AIDS and autoimmune disease. We sought to identify genetic predictors of lymphocyte levels and reasoned that these may play a role in immune-related diseases. We tested 2.3 million variants for association with five lymphocyte subsets, measured in 2538 individuals from the general population, including CD4þ T cells, CD8þ T cells, CD56þ natural killer (NK) cells, and the derived measure CD4:CD8 ratio. We identified two regions of strong association. The first was located in the major histocompatibility complex (MHC), with multiple SNPs strongly associated with CD4:CD8 ratio (rs2524054, p ¼ 2.1 3 10 À28). The second region was centered within a cluster of genes from the Schlafen family and was associated with NK cell levels (rs1838149, p ¼ 6.1 3 10 À14). The MHC association with CD4:CD8 replicated convincingly (p ¼ 1.4 3 10 À9) in an independent panel of 988 individuals. Conditional analyses indicate that there are two major independent quantitative trait loci (QTL) in the MHC region that regulate CD4:CD8 ratio: one is located in the class I cluster and influences CD8 levels, whereas the second is located in the class II cluster and regulates CD4 levels. Jointly, both QTL explained 8% of the variance in CD4:CD8 ratio. The class I variants are also strongly associated with durable host control of HIV, and class II variants are associated with type-1 diabetes, suggesting that genetic variation at the MHC may predispose one to immune-related diseases partly through disregulation of T cell homeostasis.

Journal of Cardiovascular Medicine, Nov 1, 2018

Background: A global outbreak of Mycobacterium Chimaera (MC) infections following cardiac surgery... more Background: A global outbreak of Mycobacterium Chimaera (MC) infections following cardiac surgery and linked to contaminated heater-cooler units (HCU) is currently ongoing. In 2017, since the status of this outbreak in Italy and the mitigation strategies adopted by adult cardiac surgery unit (ACSU) were not known, SICCH launched a national survey among Italian ACSUs. Methods: In Italy there are 90 ACSU across 20 regions. From May to Nov 2017 they were surveyed collecting data on a) patients diagnosed with MC infections b) ACSU workload c) used HCU models d) control measures adopted in theatres. Results: The response rate was 87.8%. The mean number of cardiac procedures at each ACSU was 508 ± 229/year and nationally the number of procedures/year exceeded 40k. In Italy 7 patients with MC infections following cardiac were reported since 2015: all had aortic or valve surgery as first procedure; the latency between first operation and infection was 2.8 ± 1.6 years. Mortality for patients requiring redo cardiac surgery was 50%. MC infections risk was 0.4–1 patient every 1000 cardiac procedures. The most common HCU model in Italy is the 3T HCU (70.9%). The most common control measures adopted were: implementing new HCU disinfection protocols, using sterile or filtrated water in the HCU and displacing HCU fans away from the patient: HCU replacement and microbiology testing were infrequent. Conclusions: In Italy the risk of contracting MC infections and the mortality reported are in line with other European countries; a significant heterogeneity exists on the mitigation strategies to prevent further MC inoculations.

International Journal of Std & Aids, Jan 10, 2019

Raltegravir (RAL) is an HIV-1 integrase strand transfer inhibitor that is well established as a c... more Raltegravir (RAL) is an HIV-1 integrase strand transfer inhibitor that is well established as a component of highly active antiretroviral therapy regimens for the treatment of adults living with human immunodeficiency virus (HIV), due to its high virological efficacy and good tolerability profile. To date, limited data are available on the use of RAL with abacavir/ lamivudine (ABC/3TC). We investigated retrospectively 62 HIV-1 infected patients managed by three Italian Infectious Diseases Outpatient Departments, including 57 treatment-experienced patients and 5 treatment-naïve patients, treated with ABC/3TC plus RAL. In all five naïve patients (100%), virological suppression was achieved and maintained , while 55 experienced patients (96.5%) maintained viral suppression at the most recent review. In the treatment-experienced patients, we observed a significant decrease in triglyceride levels (p < 0.01), while liver transaminases, renal function and cholesterol levels remained substantially stable. In the 34 treatment-experienced patients who switched from a protease inhibitor (PI)-based regimen, we observed a significant improvement of total cholesterol (p¼0.03) and triglyceride (p < 0.01) levels. No significant alterations were found on renal and liver function and serum lipid profile of treatment-naïve patients. Despite the small number of participants, results support the efficacy and safety of ABC/3TC plus RAL, either in treatment-naïve or treatment-experienced patients.

Muscle & Nerve, Aug 30, 2019

Introduction: Several viruses have been described as causes of acquired inflammatory myopathies, ... more Introduction: Several viruses have been described as causes of acquired inflammatory myopathies, however, the mechanisms by which they cause muscle disease are still unclear. The aim of this study was to describe the laboratory features of benign acute myositis in a small case series. Methods: A detailed pathological and serological analysis was performed in five African migrants who developed an acute viral myositis complicated by rhabdomyolysis. Results: Muscle biopsies clearly documented an inflammatory myopathy with histological features similar to polymyositis including CD8+ T cells surrounding and invading non-necrotic muscle fibers, CD68+ macrophages and MHC class I antigen upregulation. In addition, positivity for myositis-specific antibodies (MSA), in particular anti-aminoacyl tRNA synthetases, was found in the serum of two patients. Discussion: Our study demonstrated that T-cell mediated injury occurs in muscle of patients with acute viral myositis, and that MSA may be present in the serum of these patients.

Farmeconomia. Health economics and therapeutic pathways, Nov 6, 2017

BACKGROUND: In order to reduce/prevent combination Anti-Retroviral Therapy (cART)-related toxicit... more BACKGROUND: In order to reduce/prevent combination Anti-Retroviral Therapy (cART)-related toxicity, while maintaining its therapeutic effectiveness over time, the optimization of the antiretroviral therapy could be performed. AIM: To estimate the economic impact on the Italian National Health Service (NHS) of a cART optimization pathway as maintenance therapy in HIV-1 infected patients over one-year period. METHODS: Patient data were retrieved from the electronic medical record system in use (year 2015) in a reference HIV Center in Northern Italy. The analysis considered naïve patients and non-naïve patients. To estimate the actual ART expenditure charged to the Center we calculated the cost of cART received during 12 months for each patient. Subsequently, referring to the same patients, a "potential" cART expenditure was estimated. This potential expenditure was estimated taking in consideration the adoption of a specific optimization pathway aimed at maintaining over the time the cART efficacy. Lastly, to assess the sustainability of the optimization pathway, we compared the actual cART expenditure with the potential one. We considered only drug costs (ex-factory prices, included all discounts and VAT) from the perspective of the Italian NHS. RESULTS: In the 2015, the total expenditure for 564 enrolled HIV-1 patients treated with cART was € 4,042,983. The mean treatment cost per patient was € 7,168. If the Center adopted a specific optimization pathway, the total expenditure would be € 3,914,855 (-€ 128,128). CONCLUSIONS: From the Italian NHS's perspective, the adoption of a specific cART optimization pathway represents a cost-saving option as maintenance antiretroviral therapy in HIV-1 infected patients.

Open access journal of clinical surgery, May 17, 2021

Journal of NeuroVirology, Mar 29, 2011

Progressive multifocal leukoencephalopathy (PML) has been traditionally associated to severe immu... more Progressive multifocal leukoencephalopathy (PML) has been traditionally associated to severe immunosuppression and described mainly in highly active antiretroviral therapy (HAART)-naïve patients with a low lymphocyte CD4+ count. In the last years, some cases of PML have been described in HIV patients with a higher CD4+ count shortly after initiation of HAART and in association with the immune reconstitution inflammatory syndrome (IRIS). We report on a rare case of PML, not IRIS associated, that occurred in a HIV-positive patient with a lymphocyte CD4+ count greater than 700/µl and with an undetectable HIV viral load resulting from a long-term HAART. We describe the pathological and the ultrastructural features of the brain lesion. This case confirms that a severe immunosuppression or an IRIS is not required for the development of PML in HIV positives. The diagnosis of PML should always be considered in patients with consistent neurological symptoms, even with a high lymphocyte CD4+ level and a full viral suppression resulting from a long-term HAART.

New Microbes and New Infections

European Journal of Clinical Microbiology & Infectious Diseases, 2017

Risk assessment of central nervous system (CNS) infection patients is of key importance in predic... more Risk assessment of central nervous system (CNS) infection patients is of key importance in predicting likely pathogens. However, data are lacking on the epidemiology globally. We performed a multicenter study to understand the burden of community-acquired CNS (CA-CNS) infections between 2012 and 2014. A total of 2583 patients with CA-CNS infections were included from 37 referral centers in 20 countries. Of these, 477 (18.5%) patients survived with sequelae and 227 (8.8%) died, and 1879 (72.7%) patients were discharged with complete cure. The most frequent infecting Electronic supplementary material The online version of this article

International Journal of Antimicrobial Agents

Virological and immunological effectiveness of reduced doses of antiretrovirals has been shown in... more Virological and immunological effectiveness of reduced doses of antiretrovirals has been shown in two randomized trials and smaller studies. We have now evaluated immune activation in patients on reduced doses of antiretroviral therapy (ART) using HLA-DR+CD8+ lymphocytes as a marker of activation. In an observational, retrospective study we assessed 113 HIV-infected patients who switched from standard combined ART (cART) to reduced dose combinations (cohort 1), while maintaining virological suppression (<20 copies/mL). After a mean time of 36 months on reduced dose therapy, the mean increase in CD4+ lymphocyte numbers was 100 cell/μL (p<0.01) and the mean reduction of HLA-DR+ lymphocytes was 103 cells/μL (p<0.01). We also compared cohort 1 with a cohort of 113 virologically suppressed patients on standard cART (cohort 2). We found no signifi cant differences in the number of CD4+ lymphocytes or in immune activation (mean values of HLA-DR+ absolute number and percentage of total CD8+ lymphocytes). The results of this retrospective study did not identify any immunological differences between reduced antiretroviral dose regimens and standard cART and suggest that reduced dose regimens can progressively reduce immune activation similarly to standard cART.

International Journal of Std & Aids, Oct 21, 2020

Integrase strand transfer inhibitors (INSTIs) are a class of antiretroviral drugs with high virol... more Integrase strand transfer inhibitors (INSTIs) are a class of antiretroviral drugs with high virologic efficacy and excellent tolerability. Recent evidence showed a possible link of dolutegravir-based regimens with weight gain, and a relationship between raltegravir use and changes in adipose tissue density and metabolic abnormalities, with an increased cardiovascular risk, has been suggested. We describe a case where dolutegravir monotherapy led to a decrease in adipose tissue density.

The Lancet, May 1, 2001

Design and methodology of the CAPRICORN trial: a randomised double blind placebo controlled study... more Design and methodology of the CAPRICORN trial: a randomised double blind placebo controlled study of the impact of carvedilol on morbidity and mortality in patients with left ventricular dysfunction after myocardial infarction.

Clinical Infectious Diseases, May 23, 2019

Infectious diseases, Oct 14, 2018

European Journal of Clinical Investigation, Jul 16, 2003

Sir, Christeff and coauthors, in their recent study, have demonstrated an association between inc... more Sir, Christeff and coauthors, in their recent study, have demonstrated an association between increased serum interferon alpha and lipodystrophy (LD) in HIV1-infected subjects [1]. In the same study these authors failed to show significant differences in tumour necrosis factor alpha (TNFα ) serum levels between HIV1-positive individuals with and without lipodystrophy, although the levels of this latter cytokine were significantly higher in HIV-infected subjects than in normal people. These latter data support the hypothesis (put forward by the same French group) that antiretroviral therapy, including protease inhibitors, dysregulates the homeostasis of TNFα synthesis through reduced apoptosis of TNFα producing CD8+ CD28– T cells, and thus contributes to the development of HIV-associated lipodystrophy syndrome [2]. We report our experience in a group of 20 HIV1-infected asymptomatic individuals (15 men, age range 27–60 years, mean age 40, three previously untreated, 10 with lipodystrophy diagnosed according to a previously published clinical score) [3] on a HAART regimen, including one protease inhibitor (PI) in whom CD4, CD8 and CD8+ CD28– T cells, plasma HIV1-RNA, serum TNFα and lipid (triglycerides, high-density lipoprotein cholesterol and low-density lipoprotein cholesterol) concentrations were determined. These 20 individuals were selected from a cohort of 97 patients on the same HAART regimen on the basis of the similarities of the parameters considered later in this Letter between the two subgroups (with and without lipodystrophy). Twenty HIV1-negative healthy blood donors acted as controls. Table 1 summarizes the individuals’ data (values are given as means ± SD; significant statistical correlations [ P < 0·05] between the parameters examined within each group of subjects were determined by Student’s t -test). Duration of HAART was comparable in both subgroups (mean 61 ± 24·6 months in the LD-positive patients vs. 56 ± 18·8 months in the LD-negative patients). The mean numbers of CD4, CD8 and CD8+ CD28– T lymphocytes were also similar. HIV1 RNA levels (Chiron bDNA assay) were less than the lower limit of detection (50 copies mL − 1 ) in all but four individuals, with no significant differences between the two groups. The LD-positive subjects showed a marked increase in serum levels of triglycerides (mean 4·9 ± 3·53 vs. 1·2 ± 0·45; P < 0·0039), while levels of HDL and LDL cholesterol were comparable. Serum TNFα levels (Quantikine; R & D Systems, Minneapolis, MN) were reduced in the HIV1-infected subjects in respect of healthy, uninfected controls; the reduction was statistically significant in the LD-negative patients compared with the healthy controls ( P < 0·05), whereas no significant differences were observed between the two groups of infected individuals. Our results are therefore in sharp contrast with those of Christeff and coworkers [1]. First, we were unable to confirm a significant increase in CD8 T cells in LD-positive individuals [1–3]; second, we failed to find an increase in the number of CD8+ CD28– T cells (responsible for 80– 90% of TNFα production) [2] in LD-positive subjects; finally, we did not observe a positive correlation between the absolute numbers of these latter CD8 T-cell subpopulations and an increased serum triglycerides concentration (correlation coefficient 0·05068 in the LD-positive and 0·3822 in the LD-negative patients, P = 0·51). Although found in a limited population of HIV1-infected subjects, our results raise doubts on the proposed role of TNFα in the pathophysiologic mechanisms leading to lipodystrophy.