Pasqualina De Leo

Insulin resistance predicts rapid virological response in non-diabetic, non-cirrhotic genotype 1 HCV patients treated with peginterferon alpha-2b plus ribavirin.

BACKGROUND/AIMS The rapid decline in hepatitis C virus RNA is crucial for determining the outcome of therapy in patients with genotype 1 chronic hepatitis C. However, the variables influencing the early phase of viral decay are still largely unexplored. We aimed to assess which pre-treatment variable may predict rapid virologic response (RVR) and sustained virologic response (SVR). METHODS We evaluated 90 consecutive non-diabetic patients with genotype 1 chronic hepatitis C without cirrhosis, treated with peginterferon alpha-2b plus ribavirin. Viral load (COBAS Amplicore, Roche) was measured at 1, 4 and 12 weeks after starting treatment, and then 24 weeks after the end of treatment. RESULTS The overall SVR was 47%. The SVR in patients with RVR was 100%. Age, GGT levels, viral load, steatosis, fibrosis and HOMA-IR were significantly associated with RVR in univariate analysis. After logistic regression, HOMA-IR proved to be the strongest independent predictor of RVR (OR 0.37, 95% CI: 0.16-0.89; p=0.027), whereas fibrosis had a weaker independent association with RVR (OR 0.32, 95% CI: 0.1-1.04; p=0.057). Among the eight pre-treatment variables, both BMI and steatosis were significantly associated with HOMA-IR, either in univariate or in multivariate analyses. CONCLUSIONS Our data suggest that insulin resistance is strongly associated with RVR, thus reflecting the important role played by metabolic factors in the early phase of viral kinetics. HOMA-IR would appear to be a useful tool in predicting RVR and should be evaluated at baseline in all chronic hepatitis C patients before initiating antiviral treatment.

Clinical and virological survey of patients with hepatitis B surface antigen in an Italian region: clinical considerations and disease burden.

The aim of this study was to determine the prevalence of hepatitis B virus (HBV) infection in an Italian region, Liguria (1,572,000 inhabitants), by means of a network of 12 referral centers for liver diseases. All patients with HBV surface antigen followed throughout 2006 were included. Personal data, infectious status with risk factors, other non‐infectious risk factors for liver disease, clinical status, and treatment were the questionnaire. Four hundred forty‐five patients (71% male) were evaluated. Their median age was 48 years (range 5–84), and 83.4% were of Italian origin. Community‐acquired infection was the principal mode of HBV transmission (82.5%), followed by previous intravenous drug use (9.4%), perinatal transmission (6.3%), and transfusion‐associated transmission (1.8%). Hepatitis B e‐antigen was present in 20.4% of the patients, while co‐infections with hepatitis D virus and/or hepatitis C virus and/or human immunodeficiency virus (HIV) were observed in 18.7% of the patients. Chronic active hepatitis was present in 62.5% of the patients, cirrhosis in 13.5%, hepatocellular carcinoma in 2.2%, and 21.8% of the patients were inactive carriers of HBV. In all, 42.5% of the patients were treated with interferon or lamivudine and/or adefovir‐dipivoxil. Forty‐nine patients were co‐infected with HIV (86% on highly active antiviral therapy). Nevertheless, this study identified only 2.2% of the expected patients with HBV. Hence, it has to be reasoned that few potential infectious or treatable patients are referred to liver disease centers. HBV infection is still an underestimated health problem, and few potential infectious or treatable patients are referred to tertiary centers. J. Med. Virol. 81:1882–1886, 2009.

The ligurian human immunodeficiency virus clinical network: a web tool to manage patients with human immunodeficiency virus in primary care and multicenter clinical trials.

Background In recent years, Highly-Active Anti-Retroviral Therapies (HAARTs) have modified the Human Immunodeficiency Virus (HIV) life-cycle and the disease is now considered chronic. Consequently, a longitudinal and complex follow-up is now required for HIV positive patients during their lifetime. Moreover, patients often encounter various complications due to comorbidities, related to the immunodeficiency state and HAARTs’ side effects. Thus, HIV positive patients are involved in multicenter clinical trials (MCTs) to improve treatments and discover a preventive vaccine. Therefore, physicians require proper instruments to access comprehensive patient data for managing patients during follow-ups, and tools for data collection and analysis in MCTs. Objective The Ligurian HIV Clinical Network aims to provide physicians with a Web-tool to administrate HIV positive patients’ data within primary-care and to reuse the collected clinical information to perform MCTs in Northern Italy. Methods The key aspect of the system is a relational database which allows the storage of various types of clinical information (eg, related to HIV, cardiovascular, or hepatic diseases) in multiple formats. The modular design of the database permits a rapid insertion of new parameters without requiring any changes in the database structure. Furthermore, codes from biomedical ontologies controlled vocabularies (“Logical Observation Identifier Names and Codes”, and “International Classification of Diseases 9”) and ontologies (“Systematized Nomenclature of Medicine Clinical Terms”), units and normality ranges used by all partners participating in the project were collected to achieve a complete semantic interoperability. Accordingly, data can be automatically normalized through the z score formula and physicians can extract and correctly compare information with external statistical tools. Moreover, to respect patients’ privacy and legal issues, a local identifier, determined through an HASH cryptography algorithm, is assigned to each patient during the registration process. The database is managed by a user-friendly Web-platform which allows quick access to information during medical examinations and the reusing of the collected data for present and future MCTs. Furthermore, a bidirectional middleware was created in order to import/export information through HL7 messaging. Hence, data can be manually entered by physicians or automatically collected within HL7-compliant Hospital Information systems. Results Presently, the direct storage of patients’ information from the San Paolo Hospital (Savona, Italy), and San Martino and Galliera hospitals in Genoa is in a test phase. Currently, 8 centers of Infectious Diseases (located in Liguria and Piedmont) are participating in the project and almost 400 HIV positive patients have been recorded in the system. Patient data has been used for primary care and research purposes. Currently, there are 4 on-going MCTs and preliminary results have already been presented at International HIV congresses. Conclusions The Web-platform allows effective management, sharing and reuse of information within primary care and clinical research. In the future it is planned to share the clinical information from this network with other HL7-compliant workgroups and to extend the platform to other infective diseases (eg, hepatitis).

CD8+CD28−CD127loCD39+ regulatory T-cell expansion: A new possible pathogenic mechanism for HIV infection?

Background: HIV‐associated immunodeficiency is related to loss of CD4+ T cells. This mechanism does not explain certain manifestations of HIV disease, such as immunodeficiency events in patients with greater than 500 CD4+ T cells/&mgr;L. CD8+CD28−CD127loCD39+ T cells are regulatory T (Treg) lymphocytes that are highly concentrated within the tumor microenvironment and never analyzed in the circulation of HIV‐infected patients. Objectives: We sought to analyze the frequency of CD8+CD28−CD127loCD39+ Treg cells in the circulation of HIV‐infected patients. Methods: The frequency of circulating CD8+CD28−CD127loCD39+ Treg cells was analyzed and correlated with viral load and CD4+ T‐cell counts/percentages in 93 HIV‐1–infected patients subdivided as follows: naive (n = 63), elite controllers (n = 19), long‐term nonprogressors (n = 7), and HIV‐infected patients affected by tumor (n = 4). The same analyses were performed in HIV‐negative patients with cancer (n = 53), hepatitis C virus–infected patients (n = 17), and healthy donors (n = 173). Results: HIV‐infected patients had increased circulating levels of functional CD8+CD28−CD127loCD39+ Treg cells. These cells showed antigen specificity against HIV proteins. Their frequency after antiretroviral therapy (ART) correlated with HIV viremia, CD4+ T‐cell counts, and immune activation markers, suggesting their pathogenic involvement in AIDS‐ or non–AIDS‐related complications. Their increase after initiation of ART heralded a lack of virologic or clinical response, and hence their monitoring is clinically relevant. Conclusion: HIV infection induces remarkable expansion of CD8+CD28−CD127loCD39+ Treg cells, the frequency of which correlates with both clinical disease and signs of chronic immune cell activation. Monitoring their frequency in the circulation is a new marker of response to ART when effects on viremia and clinical response are not met.

Therapeutic management of chronic hepatitis B in clinical practice: A region-wide survey

Goals: To characterize the clinical and treatment pattern in a large population of hepatitis B virus (HBV) patients managed at tertiary referral centers in clinical practice. Background: Successful treatment, either with interferon (IFN) or nucleos(t)ide analogs (NUCs), of chronic HBV infection is associated with improved long-term patient outcome. However, in clinical practice, the actual management of these patients is not well characterized, and data regarding treatment pattern in this setting are lacking. Methods: In this cross-sectional study, we evaluated 505 patients chronically infected with HBV alone and who had at least 1-year follow-up. We assessed indication to, rate of, and type of treatment as well as the characteristics of treated patients. Results: Overall prevalence of positivity for HBe antigen was 19.3%, and the majority of patients had chronic hepatitis (47.5%). Non-Italian patients represented approximately one third of the population (27.1%). Among patients with indication to antiviral therapy (n=318), treatment was actually carried out in 264 patients (83.0%), prevalently with NUCs (65.9%). IFN-treated patients were younger (P<0.001), more frequently male (P=0.025) and HBeAg positive (P=0.003), and less frequently cirrhotics (P<0.001) as compared with patients treated with NUCs. Conclusions: In a geographical area with a low positivity for HBe antigen, antiviral therapy is actually carried out in the majority of patients who have indication to treatment, prevalently with NUCs, whereas IFN treatment is more frequently carried out in young, HBe antigen–positive patients who do not have advanced liver disease.

‘Emergency exit’ of bone-marrow-resident CD34 + DNAM-1 bright CXCR4 + -committed lymphoid precursors during chronic infection and inflammation

During chronic inflammatory disorders, a persistent natural killer (NK) cell derangement is observed. While increased cell turnover is expected, little is known about whether and how NK-cell homeostatic balance is maintained. Here, flow cytometric analysis of peripheral blood mononuclear cells in chronic inflammatory disorders, both infectious and non-infectious, reveals the presence of a CD34+CD226(DNAM-1)brightCXCR4+ cell population displaying transcriptional signatures typical of common lymphocyte precursors and giving rise to NK-cell progenies with high expression of activating receptors and mature function and even to α/β T lymphocytes. CD34+CD226brightCXCR4+ cells reside in bone marrow, hardly circulate in healthy donors and are absent in cord blood. Their proportion correlates with the degree of inflammation, reflecting lymphoid cell turnover/reconstitution during chronic inflammation. These findings provide insight on intermediate stages of NK-cell development, a view of emergency recruitment of cell precursors, and upgrade our understanding and monitoring of chronic inflammatory conditions.

Relationship between innate immunity, soluble markers and metabolic-clinical parameters in HIV+ patients ART treated with HIV-RNA<50 cp/mL.

The persistence of immune activation and inflammation in HIV patients with HIV‐RNA (VL) undetectable causes many co‐morbidities [ 1 – 3 ]. The aim of this study is to correlate monocytes (m) and NK cell activation levels, soluble markers and oxidative stress with clinical, biochemical and metabolic data in HIV‐1 infected patients with VL≤50 copies (cp)/mL on antiretroviral therapy.

Cost per care of the first year of direct antiviral agents in the Liguria Region: a multicenter analysis

Aims Despite the remarkable efficacy shown in clinical practice, concerns have been raised about the costs associated with direct antiviral agent (DAA) therapy. This article presents the real-life costs for DAA treatment sustained by the Italian National Health Service in the Liguria Region (Northern Italy). Methods A retrospective analysis of the cost per care sustained for DAA treatment, relating to the period from January 1 to December 31, 2015 in five centers in Liguria was performed. All patients undergoing DAA-based treatments for hepatitis C virus (HCV) infection were enrolled. On-treatment costs included: HCV treatment, laboratory test, outpatient services, attended visits, drugs used for the management of adverse events (erythropoietin, albumin or red blood cell packs) and inpatient service admissions. Results In total, 327 patients were enrolled. No difference in terms of sustained virologic response (SVR) rate among different treatments was reported. The majority (85.0%) of patients did not report any side effects and only 15 (4.6%) required hospital admission. Forty-two patients (12.8%) required high-cost drugs for the management of adverse events. The overall cost sustained was €14,744,433. DAA±ribavirin (RBV) accounted for the wide majority of this cost (98.9%; €14,585,123). Genotype (GT) 1, the most commonly treated GT, was associated with an average cost of €43,445 per patient. Detailed analysis of the costs for GT 1 showed the treatment based on ritonavir boosted paritaprevir/ombitasvir + dasabuvir±RBV with an average cost of €24,978 (RBV+) and €25,448 (RBV−) per patient was the most cost-effective. The average cost per SVR was €48,184. Once again, the ritonavir boosted paritaprevir/ombitasvir + dasabuvir regimen was associated with the lowest cost/SVR (€25,448/SVR [GT 1b] and similar results for other GTs). Conclusion Antiviral regimen is the major contributor to costs in the treatment of HCV infection. Appropriate regimen selection could result in a major cost saving, which can be reinvested to allow more patients to be treated.

Hepatitis B Reactivation in a HBsAg-Negative, HBcAb-Positive Patient Receiving Fludarabine for the Treatment of Chronic Lymphocytic Leukaemia

Hepatitis B virus (HBV) reactivation is an increasingly recognized cause of morbidity and mortality in patients undergoing chemotherapy. In haematology, the risk of reactivation of B hepatitis among HBsAg-positive patients has been documented; therefore, use of lamivudine prophylaxis is recommended before starting chemotherapy. Differently, for HBsAg-negative patients with markers of previous HBV infection (i.e., presence of isolated anti-HBc positivity) (anticore patients) management strategies are not univocal. We describe a rare case of HBV reactivation in an anticore patient after fludarabine therapy for chronic lymphocytic leukaemia. The patient fully recovered after a 6-month course of lamivudine with persistent HBV-DNA clearance and loss of HBsAg. The most important feature of this case is that fludarabine alone infrequently determines HBV reactivation, especially in anticore patients. Therefore, we suggest that patients candidates to receive fludarabine therapy should be considered for lamivudine prophylaxis, not only if HBsAg-positive, but even if anticore-positive only.