M. Fasano

Virological response to entecavir is associated with a better clinical outcome in chronic hepatitis B patients with cirrhosis

Objective Entecavir (ETV) is a potent inhibitor of viral replication in chronic hepatitis B and prolonged treatment may result in regression of fibrosis. The aim of this study was to investigate the effect of ETV on disease progression. Design In a multicentre cohort study, 372 ETV-treated patients were investigated. Clinical events were defined as development of hepatocellular carcinoma (HCC), hepatic decompensation or death. Virological response (VR) was defined as HBV DNA <80u2005IU/ml. Results Patients were classified as having chronic hepatitis B without cirrhosis (n=274), compensated cirrhosis (n=89) and decompensated cirrhosis (n=9). The probability of VR was not influenced by severity of liver disease (p=0.62). During a median follow-up of 20u2005months (IQR 11–32), the probability of developing clinical events was higher for patients with cirrhosis (HR 15.41 (95% CI 3.42 to 69.54), p<0.001). VR was associated with a lower probability of disease progression (HR 0.29 (95% CI 0.08 to 1.00), p=0.05) which remained after correction for established risk factors such as age. The benefit of VR was only significant in patients with cirrhosis (HR 0.22 (95% CI 0.05 to 0.99), p=0.04) and remained after excluding decompensated patients (HR 0.15 (95% CI 0.03 to 0.81), p=0.03). A higher HBV DNA threshold of 2000u2005IU/ml was not associated with the probability of disease progression (HR 0.20 (95% CI 0.03 to 1.10), p=0.10). Conclusion VR to ETV is associated with a lower probability of disease progression in patients with cirrhosis, even after correction for possible baseline confounders. When using a threshold of 2000u2005IU/ml, the association between viral replication and disease progression was reduced, suggesting that complete viral suppression is essential for nucleoside/nucleotide analogue treatment, especially in patients with cirrhosis.

Lack of full CD8 functional restoration after antiviral treatment for acute and chronic hepatitis C virus infection

Background Hepatitis C virus (HCV) persistence is associated with impaired CD8 functions. Whether functional restoration of CD8 T cells chronically exposed to antigen can be obtained once the antigen is removed remains to be clarified. Objective To determine whether clearance of HCV by antiviral treatment can fully restore the antiviral function of HCV-specific CD8 cells. Design Peripheral blood HCV-, Flu- and cytomegalovirus (CMV)-specific CD8 cells were quantified by tetramer staining in 28 patients whose HCV infection resolved after peginterferon or peginterferon/ribavirin treatment for either acute or chronic hepatitis and in eight subjects with acute HCV infection which resolved spontaneously for comparison. HCV-specific CD8 cells were evaluated for their phenotypic and functional characteristics by comparing different patient groups and CD8 cells with different viral specificities in the same patients. Results Sustained viral response (SVR) did not lead to full maturation of a functional memory CD8 cell response. In particular, SVR in chronic infection was associated with a greater level of T cell dysfunction than responders after acute infection, who showed HCV-specific CD8 responses comparable to those of spontaneous resolvers but weaker than those of Flu-specific CD8 cells. Higher programmed death (PD)-1 expression was detected on HCV than on Flu- and CMV-specific CD8 cells and the effect of PD-1/PD-L1 blockade was better in SVRs after chronic than after acute HCV infection. Conclusion A better restoration of HCV-specific CD8 function was detectable after SVR in patients with acute hepatitis than in those with chronic disease. Thus, the difficulty in achieving a complete restoration of the antiviral T cell function should be considered in the design of immunomodulatory therapies.

HBV DNA suppression and HBsAg clearance in HBeAg negative chronic hepatitis B patients on lamivudine therapy for over 5 years

BACKGROUND & AIMSnIn long-term responder patients, it is unclear whether lamivudine (LAM) monotherapy should be continued or switched to a high-genetic-barrier analogue. This study aims at assessing LAM efficacy over a 5-year period and the residual risk of drug resistance. The rate of HBsAg clearance and LAM long-term safety profile were also evaluated.nnnMETHODSnOne hundred and ninety-one patients with chronic HBeAg-negative hepatitis B successfully treated with LAM monotherapy for at least 5 years were included. Biochemical and virological tests were assessed every 3 months in all patients and HBsAg quantification was performed in 45/191. Reverse-transcriptase (RT) region was directly sequenced in virological breakthrough patients.nnnRESULTSnOne hundred and ninety-one patients (148 males, median age 53 years, 72 with compensated cirrhosis) responding to 60-month LAM monotherapy continued to receive LAM monotherapy beyond the initial 5 years and were followed for an additional 36-month median period (range 1-108). Virological response was maintained in 128/191 patients (67%) and HBsAg clearance was observed in 15/128 (11.7%) after a 32-month median period (range 1-65). The 63 remaining patients (33%) showed virological breakthrough after a 15-month median treatment (range 1-78). RT region analysis was performed in 38/63 breakthrough patients and LAM resistant mutations were found in 37/38. No significant side effects were observed.nnnCONCLUSIONSnIn long-term responder patients, continuation of LAM monotherapy resulted in persistent viral suppression in most cases with undetectable HBV DNA by real-time PCR; moreover, 11.7% of these patients cleared HBsAg. Selection of LAM resistance, however, can still occur even after successful long-term therapy, thus emphasising the importance of a careful virological monitoring.

Chronic hepatitis B: Advances in treatment.

Treatment of chronic hepatitis B (CHB) has markedly improved in the last 15 years due to the availability of direct antivirals which greatly increase therapeutic options. Currently, there are two classes of agents licensed for CHB treatment: standard or pegylated interferon alpha (IFN or Peg-IFN) and five nucleoside/nucleotide analogues (NAs). Long-term treatment with NAs is the treatment option most often used in the majority of CHB patients. Entecavir and tenofovir, the most potent NAs with high barrier to resistance, are recommended as first-line monotherapy by all major treatment guidelines and can lead to long-lasting virological suppression, resulting in histological improvement or reversal of advanced fibrosis and reduction in disease progression and liver-related complications. In this review, we focus on current treatment strategies of chronic hepatitis B and discuss the most recent efficacy and safety data from clinical trials and real life clinical practice. Recent findings of response-guided approaches are also discussed.

Bone and kidney toxicity induced by nucleotide analogues in patients affected by HBV-related chronic hepatitis: a longitudinal study

OBJECTIVESnNucleotide analogues may promote renal and bone toxicity. The aim of the present study was to evaluate markers of osteorenal toxicity in patients affected by hepatitis B virus-related chronic hepatitis treated with lamivudine plus adefovir who were switched to tenofovir.nnnPATIENTS AND METHODSnWe evaluated 60 consecutive patients at the time of the switch of treatment and after 1, 3, 6, 9 and 12 months. The mean baseline estimated glomerular filtration rate (eGFR) was 89.3 ± 19.0 mL/min/1.73 m(2).nnnRESULTSnDuring the study period we observed a reduction in mean eGFR up to 6 months after switching to tenofovir, and this remained stable for the last two timepoints. At the end of study, the mean eGFR was 82.6 ± 21.5 mL/min/1.73 m(2), a reduction of 7.5%. The mean baseline proteinuria was 202.6 ± 237.6 mg/24 h. Microhaematuria was observed in 22.6% of patients and hypophosphataemia in 18.6%. After 1 month of tenofovir, we observed a worsening of serum phosphate and parathyroid hormone levels, haemoglobinuria and 24 h proteinuria. After 3 and 12 months of tenofovir, these data tended to recover to baseline levels. A total of 92.6% of patients at baseline had hypovitaminosis D. After supplementation with cholecalciferol, this percentage decreased significantly. We observed a reduced bone mineral density (BMD) in 52.7% of patients at baseline; this increased to 77.8% after 6 months of tenofovir, but at the last timepoint the percentage of patients with a reduced BMD had fallen to a level above the baseline.nnnCONCLUSIONSnIn conclusion, patients exposed to lamivudine plus adefovir showed relevant osteorenal damage. The switch to tenofovir provoked a slight reduction in eGFR that stabilized after 6 months. The reduced BMD at baseline did not worsen under tenofovir treatment.

Hepatitis B and immigrants: a SIMIT multicenter cross-sectional study

BackgroundThe continuing migration of individuals from geographic areas with high/medium endemicity has determined the arrival of new chronic hepatitis B virus (HBV) carriers in Italy. The magnitude of this phenomenon and clinical/virological features of HBsAg-positive migrants remain not very well defined.AimsTo evaluate the proportion of HBsAg-positive immigrants enrolled in this multicenter Società Italiana di Malattie Infettive e Tropicali (SIMIT) cross-sectional study and to compare the characteristics of chronic hepatitis B infection in migrants to those of Italian carriers.MethodsFrom February 1 to July 31 2008, anonymous data were obtained from all HBsAg-positive patients aged ≥18xa0years observed at 74 Italian centers of infectious diseases.ResultsOf the 3,760 HBsAg-positive subjects enrolled, 932 (24.8xa0%) were immigrants, with a prevalent distribution in central to northern Italy. The areas of origin were: Far East (37.1xa0%), Eastern Europe (35.4xa0%), Sub-Saharan Africa (17.5xa0%), North Africa (5.5xa0%), and 4.5xa0% from various other sites. Compared to Italian carriers, migrants were significantly younger (median age 34 vs. 52 years), predominantly female (57.5 vs. 31xa0%), and most often at first observation (incident cases 34.2 vs. 13.3xa0%). HBeAg-positives were more frequent among migrants (27.5 vs. 14xa0%). Genotype D, found in 87.8xa0% of Italian carriers, was present in only 40xa0% of migrants, who were more frequently inactive HBV carriers, with a lower prevalence of chronic hepatitis, cirrhosis, and hepatocellular carcinoma (HCC). Only 27.1xa0% of migrants received antiviral treatment compared to 50.3xa0% of Italians.ConclusionsTwenty-five percent of all HBV carriers examined at Italian centers was composed of immigrants with demographic, serological, and virological characteristics that differed from those of natives and appeared to have an inferior access to treatment.

Development and specificities of anti-interferon neutralizing antibodies in patients with chronic hepatitis C treated with pegylated interferon-α

Only limited data are available on the development of neutralizing antibodies (NAB) in patients with chronic hepatitis C (CHC) treated with pegylated interferon-α (PEG-IFN-α). The aim of this study was to evaluate the immunogenicity of PEG-IFN-α when administered to CHC patients who had or had not previously received standard IFN-α therapy. In addition, the specificities of NAB, together with the ability of leucocyte (LE) -IFN-α to re-establish therapeutic responsiveness in NAB-positive patients, were evaluated. NAB were assessed using a quantitative, standardized, virus-induced cytopathic effect assay. The seroconversion rate to PEG-IFN-α was higher in patients who had received previous standard IFN-α treatment than in those treated exclusively with PEG-IFN-α. Also, NAB produced during PEG-IFN-α therapy were unable to neutralize LE-IFN-α entirely, even though they can neutralize several IFN-α subtypes. In addition, the results indicate that a change to LE-IFN-α therapy can be associated with restoration of clinical responses in NAB-positive patients who had become resistant after showing an initial response to PEG-IFN-α treatment. This study emphasizes the importance of evaluating NAB development in CHC patients who become resistant to PEG-IFN-α treatment, and suggests management alternatives for patients who develop NAB.

525 TENOFOVIR MONOTHERAPY FOR NAÏVE PATIENTS WITH CHRONIC HEPATITIS B: A MULTICENTER EUROPEAN STUDY IN CLINICAL PRACTICE IN 302 PATIENTS FOLLOWED FOR 30 MONTHS

Pinzello8, Alessia M. Giorgini9, Massimo Zuin9, Andrea Salmi10, Paolo Del Poggio11, Francesca De Filippi12, Savino Bruno12, Luisa Pasulo13, Stefano Fagiuoli13, Marco Andreoletti14, Agostino Colli14, Francesco Fumagalli Maldini15, Maria Milanese15, Alberto Eraldo Colombo16, Giorgio Bellati16, Elena Angeli17, Carlo Magni17, Guido A. Gubertini17, Giuliano Rizzardini17, Massimo Fasano18, Teresa Santantonio19, Natalia M. Terreni20, Giancarlo Spinzi20, Floriana Facchetti1, Federica Invernizzi1, Massimo Colombo1 Tenofovir monotherapy for naive patients with chronic hepatitis B: a multicenter European study in clinical practice in 302 patients followed for 30 months

522 MAINTAINED VIRAL SUPPRESSION AND EXCELLENT SAFETY PROFILE OF ENTECAVIR MONOTHERAPY IN 418 NUC-NAÏVE PATIENTS WITH CHRONIC HEPATITIS B: A 4-YEAR FIELD PRACTICE, MULTICENTER STUDY

Angela Testa7, Pasquale Narciso7, Giorgio Antonucci7, Maria Vinci8, Giovambattista Pinzello8, Erika Fatta9, Silvia Fargion9, Paolo Del Poggio10, Barbara Coco11, Maurizia R. Brunetto11, Marco Andreoletti12, Agostino Colli12, Massimo Fasano14, Teresa Santantonio13, Guido Colloredo15, Luisa Pasulo16, Stefano Fagiuoli16, Alberto Eraldo Colombo17, Giorgio Bellati17, Francesco Fumagalli Maldini18, Maria Milanese18, Massimo Pozzi19, Natalia M. Terreni20, Giancarlo Spinzi20, Michela Quagliuolo21, Mauro Borzio21, Giovanna Lunghi22, Massimo Colombo1 Maintained viral suppression and excellent safety profile of entecavir monotherapy in 418 NUCnaive patients with chronic hepatitis B : a 4-year field practice, multicenter study

Preliminary Data From the Study of Coagulative Profile of HIV Infected Individuals Suggest a Role For Point Mutations in the Gene in Protein S Deficiency in Individuals Undergoing Highly Antiretroviral Therapy

Background: HIV infection is a known prothrombotic condition but factors involved are still controversial. A role for antiretrovirals, especially protease inhibitors, was advocated. Objectives: The study aimed to analyze the levels of anticoagulant proteins in virally suppressed HIV-infected subjects treated with different anti-retroviral regimens. Materials and Methods: Forty-four patients were included in the study. C and PS, D-Dimers and Fibrinogen levels were determined as well as APC-resistance. PROS1 gene was sequenced in a group of patient. Results: Twelve of the 44 subjects (27%) showed reduced levels of PS, while lower levels of PC were found only in 2 patients (4,5%). No difference in the mean values of PC and PS was found stratifying the study population by antiretroviral regimen administrated (p>0.05). Three patients had higher levels of D-Dimer concentrations and in two of these patients, an association between higher D-Dimer values and lower levels of PS was observed; but however no correlation was found by statistical analysis. PROS1 gene analysis was performed in 26 of the 44 HIV-1 patients and the subjects with low levels of PS had mutation in the fifteen exon of PROS 1 gene. While among individuals with normal levels, this mutation was observed only in 8/18 (44%) of the cases (p=0,0072). Conclusion: The majority of patients with low PS levels also had mutations in the fifteen exon of PROS 1 gene. Genetic determinants, deserving further investigations, rather than antiretrovirals might cause PS deficiency in HIV-1 positive patients.