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Aim: In long-term nucleos(t)ide analog (NA) suppressed patients with chronic hepatitis B (CHB), hepatocellular carcinoma (HCC) can still develop. Few data exist on the incidence and the predictors of HCC development beyond the first five years in long-term treated patients. To assess the prevalence, incidence, and risk factors for HCC development in a real-life cohort of successfully NA-treated CHB patients for more than five years. Methods: All CHB patients under NAs for ≥ 60 months with stable virologic response were enrolled. HCC surveillance was carried out using liver ultrasound and dosing of serum alpha-fetoprotein every year in patients with CHB and every six months in cirrhotic patients. The baseline PAGE-B score was calculated for each patient. Results: 343 patients (76% male, 86% HBeAg-negative, 30% cirrhotic) were enrolled. During a median (IQR) follow-up of 144 (105-182) months, 21 patients (6%) developed HCC despite virologic suppression (incidence rate 40 cases/1000 person-years follow-up). In multivariate analysis, higher PAGE B score [adjusted Hazard Ratio, aHR 1.26 (95%CI: 1.13-1.54), P = .022] and cirrhosis [aHR 9.71 (95%CI: 2.02-46.48), P = .005] were predictors of HCC development. PAGE B score showed a significant association with HCC (R2 0.225, P < .001) and good prognostic capacity (AUC 0.863) of HCC. Conclusions: Our results confirm that in successfully NA-treated CHB patients, sustained viral replication suppression does not abolish the risk of HCC. The PAGE-B score could be a useful tool for identifying high-risk subjects.

Introduction: The prevention of transmission of HIV infection is based on the regular and correct use of condom and studies on transmission rates are generally based on the self-report of condom use. However, consistent data on different population suggest that this often leads to overreporting possibly due to social desirability. In addition, self-report of condom use does not consider improper use or breakage. Methods: Vaginal biomarkers were proposed to detect exposure to semen and among these detection of chromosome Y DNA (Yc) appeared promising in different research settings. Here, we searched for Yc in vaginal swabs of 33 Italian women, engaged in a regular heterosexual relationship with a HIV serodiscordant partner and reporting a regular use of condom during sexual intercourses. Results & Discussion: In 10 (30.3%) women Yc was detected, especially if the infected partner was male and if the couple did not have sons. This is confirmed in Italian heterosexual women and is already demonstrated in other populations: behavioural counselling is not always a valid tool and the self-reported use of condom is not fully reliable. Conclusion: Further studies could help in the future to individuate more effective preventive strategies for both HIV and sexually transmitted infections.

BACKGROUND Chronic hepatitis B virus (HBV) infection remains a primary cause of morbidity and mortality worldwide. AIM The study is aimed at updating the clinical and epidemiological profile of chronic HBV infection in Italy. METHODS A cross-sectional multicenter prospective study enrolled consecutive HBsAg positive patients seen in 73 Italian centers in the period 2012-2015. Individual patient data were collected using an electronic platform and analyzed using standard statistical methods. RESULTS Among 2877 HBsAg positive individuals (median age 49.8 years, 68% males), 27% were non-Italian natives (NINs); 20% had chronic infection, 58.5% chronic hepatitis and 21.5% cirrhosis. Among NINs, age was younger, male gender was less prevalent and liver disease less advanced than in Italians (all p

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.

Background Migrants in Italy are prevalently young adults, with a higher risk of sexual transmitted infections (STI) and HIV infection. Promoting consistent as well as correct use of condoms could reduce failure rate due to their improper use. The aim of our study was to evaluate Condom Use Skills among a migrant population recently landed in Italy, hosted in a government center for asylum seekers. Methods The study sample was composed of 80 male migrants. Sanitary trained interviewers submitted a questionnaire to participants to investigate age, provenience, marital status, educational level and knowledge about transmission and prevention of HIV/STI. Then, we assessed participants’ level of condom use skill with the Condom Use Skills (CUS) measure by using a wooden penile model. The interviewer filled in a checklist and assigned 1 point for correct demonstration of each behavior that may prevent condom failure during sex. Results Participants’ median age was 26 years and the sample was composed of 54 migrants from sub-Saharan Africa and 26 from Middle East. Most of them were married, with a lower middle level of education, up to 8 or 5 years. Half of the sample achieved the highest score in the questionnaire and our CUS showed a large number of people with middle high score classes. The Spearman’s rho was 0.30, therefore answers to the questionnaire and CUS score appeared correlated (p

BACKGROUND Suppression of hepatitis B virus (HBV) replication with nucelos(t)ide analogues should be considered for patients with chronic hepatitis D virus (HDV) infection and ongoing HBV replication. AIM To verify the clinical outcome after long-term entecavir or tenofovir treatment in patients with advanced fibrosis/cirrhosis, ineligible to peg-interferon therapy. METHODS Patients were prospectively followed-up at 3-6 month intervals; measured outcomes were decompensation, hepatocellular carcinoma (HCC), liver transplant and liver related death. HBV monoinfected patients receiving the same treatment served as reference after 1:1 matching by age, gender, platelet count, albumin level, bilirubin and INR. RESULTS 56 HDV patients (48 with cirrhosis; median follow-up 50 months) were enrolled; all achieved HBV DNA suppression. Death or liver transplant occurred in 19 patients, with a rate (n/1000 patient-months) of 2.92 in HDV patients vs 0.38 in HBV monoinfected patients (P

Background and Aims: Tenofovir disoproxil fumarate (TDF) is recommended for chronic hepatitis B (CHB) treatment, but it may induce kidney dysfunction whose management is not yet known. This Italian, multicentre, retrospective study aimed to assess the efficacy and safety of switching to entecavir (ETV) patients who developed TDF-associated glomerular and/or tubular dysfunction. Methods: A total of 103 TDF-treated patients were included as follows: age 64years, 83% male, 49% cirrhotics, 98% with undetectable HBV DNA, 47% with previous lamivudine resistance (LMV-R) and 71% previously treated with adefovir. Twenty-nine (28%) were switched to ETV because estimated glomerular filtration rate (eGFR MDRD ) was

BACKGROUND AND AIM: The incidence and consequences of flares during first-line nucleos(t)ide analogue therapy are largely unknown. We aimed to investigate the incidence and outcome of alanine aminotransferase (ALT) flares during long-term entecavir (ETV) in chronic hepatitis B (CHB). METHODS: CHB patients treated with ETV monotherapy from 11 European centers were studied. Flare was defined as \textgreater 3x increase in ALT compared with baseline or lowest on-treatment level and an absolute ALT \textgreater 3x ULN. Flares were designated as host-induced (preceded by hepatitis B virus (HBV)-DNA decline), virus-induced (HBV-DNA increase), or indeterminate (stable HBV-DNA). RESULTS: Seven hundred and twenty-nine patients were treated with ETV for median of 3.5 years. Thirty patients developed a flare with cumulative incidence of 6.3% at year 5. Baseline hepatitis B e antigen (HBeAg)-positivity (HR 2.84; P = 0.005) and high HBV-DNA (Hazard ratio (HR) 1.30; P = 0.003) predicted flares. There were 12 (40%) host-induced, 7 (23%) virus-induced, and 11 (37%) indeterminate flares. Host-induced flares occurred earlier than virus-induced (median: 15 vs 83 weeks; P = 0.027) or indeterminate flares (15 vs 109 weeks; P = 0.011). Host-induced flares were associated with biochemical remission, and HBeAg (n = 3) and hepatitis B surface antigen (n = 2) seroconversions were exclusively observed among patients with these flares. Virus-induced flares were associated with ETV resistance (n = 2) and non-compliance (n = 1). CONCLUSION: The incidence of ALT flares during ETV was low in this real-life cohort. ETV can be safely continued in patients with host-induced flares. Treatment adherence and drug resistance must be assessed in patients with virus-induced flares

Chronic hepatitis B virus (HBV) infection remains a primary cause of morbidity and mortality worldwide.The study is aimed at updating the clinical and epidemiological profile of chronic HBV infection in Italy.A cross-sectional multicenter prospective study enrolled consecutive HBsAg positive patients seen in 73 Italian centers in the period 2012-2015. Individual patient data were collected using an electronic platform and analyzed using standard statistical methods.Among 2877 HBsAg positive individuals (median age 49.8 years, 68% males), 27% were non-Italian natives (NINs); 20% had chronic infection, 58.5% chronic hepatitis and 21.5% cirrhosis. Among NINs, age was younger, male gender was less prevalent and liver disease less advanced than in Italians (all p 0.0001). HBeAg positive cases were 23.6% among NINs vs 8.2% in Italians (p 0.0001); HDV coinfections 11.1% vs 7.3% (p = 0.006) and HCV coinfections 2.3% vs 4.2% (p = 0.017), respectively. Anti-HDV or anti-HCV antibodies were detected more frequently in patients with cirrhosis. Fifty percent of NINs with cirrhosis were aged below 45 years.The study offers an insight into the evolving burden of chronic hepatitis B virus infection in the near future and highlights new territories for public health interventions.

An important requirement for a state-of-the-art hepatitis B surface antigen (HBsAg) screening assay is reliable detection of mutated HBsAg. Currently, there is a striking shortage of data regarding the detection rates of in vivo HBsAg mutations for these clinically important assays. Therefore, we compared the detection rates of four commercial HBsAg screening assays using a global cohort of 1553 patients from four continents with known HBV genotypes. These samples, which represent the broadest spectrum of known and novel HBsAg major hydrophilic region (MHR) mutations to date, were analyzed for the presence of HBsAg using the Roche Elecsys® HBsAg II Qualitative, Siemens ADVIA Centaur XP HBsAg II, Abbott Architect HBsAg Qualitative II and DiaSorin Liaison® HBsAg Qualitative assays, respectively. Of the 1553 samples, 1391 samples could be sequenced; of these, 1013 (72.8%) carried at least one of the 345 currently known amino acid substitutions (distinct HBsAg mutation) in the HBsAg MHR. All 1553 patient samples were positive for HBsAg using the Elecsys® HBsAg II Qual assay, with a sensitivity (95% confidence interval) of 99.94% (99.64%-100%), followed by the Abbott Architect 99.81% (99.44%-99.96%), Siemens ADVIA 99.81% (99.44%-99.96%) and DiaSorin Liaison® 99.36% (98.82%-99.69%) assays, respectively. Our results indicate that the Elecsys® HBsAg II Qual assay exhibits the highest sensitivity among the commercial HBsAg screening assays, and demonstrate that its capacity to detect HBV infection is not compromised by HBsAg MHR mutants.

Background Hepatocellular carcinoma (HCC) risk-scores may predict HCC in Asian entecavir (ETV)-treated patients. We aimed to study risk factors and performance of risk scores during ETV treatment in an ethnically diverse Western population. Methods We studied all HBV monoinfected patients treated with ETV from 11 European referral centres within the VIRGIL Network. Results A total of 744 patients were included; 42% Caucasian, 29% Asian, 19% other, 10% unknown. At baseline, 164 patients (22%) had cirrhosis. During a median follow-up of 167 (IQR 82-212) weeks, 14 patients developed HCC of whom nine (64%) had cirrhosis at baseline. The 5-year cumulative incidence rate of HCC was 2.1% for non-cirrhotic and 10.9% for cirrhotic patients (p

The diversity of the hepatitis B surface antigen (HBsAg) has a significant impact on the performance of diagnostic screening tests and the clinical outcome of hepatitis B infection. Neutralizing or diagnostic antibodies against the HBsAg are directed towards its highly conserved major hydrophilic region (MHR), in particular towards its "a" determinant subdomain. Here, we explored, on a global scale, the genetic diversity of the HBsAg MHR in a large, multi-ethnic cohort of randomly selected subjects with HBV infection from four continents. A total of 1553 HBsAg positive blood samples of subjects originating from 20 different countries across Africa, America, Asia and central Europe were characterized for amino acid variation in the MHR. Using highly sensitive ultra-deep sequencing, we found 72.8% of the successfully sequenced subjects (n = 1391) demonstrated amino acid sequence variation in the HBsAg MHR. This indicates that the global variation frequency in the HBsAg MHR is threefold higher than previously reported. The majority of the amino acid mutations were found in the HBV genotypes B (28.9%) and C (25.4%). Collectively, we identified 345 distinct amino acid mutations in the MHR. Among these, we report 62 previously unknown mutations, which extends the worldwide pool of currently known HBsAg MHR mutations by 22%. Importantly, topological analysis identified the "a" determinant upstream flanking region as the structurally most diverse subdomain of the HBsAg MHR. The highest prevalence of "a" determinant region mutations was observed in subjects from Asia, followed by the African, American and European cohorts, respectively. Finally, we found that more than half (59.3%) of all HBV subjects investigated carried multiple MHR mutations. Together, this worldwide ultra-deep sequencing based genotyping study reveals that the global prevalence and structural complexity of variation in the hepatitis B surface antigen have, to date, been significantly underappreciated.

Background & Aims: Modulation of dendritic cell (DC) function has been theorized as one of the mechanisms used by hepatitis C virus (HCV) to evade the host immune response and cause persistent infection. Methods: We used a range of cell and molecular biology techniques to study DC subsets from uninfected and HCV-infected individuals. Results: We found that patients with persistent HCV infection have lower numbers of circulating myeloid DC and plasmacytoid DC than healthy controls or patients who spontaneously recovered from HCV infection. Nonetheless, DC from patients with persistent HCV infection display normal phagocytic activity, typical expression of the class I and II HLA and co-stimulatory molecules, and conventional cytokine production when stimulated to mature in vitro. In contrast, they do not display the strong switch from immunoproteasome to standard proteasome subunit expression and the upregulation of the transporter-associated proteins following stimulation, which were instead observed in DC from uninfected individuals. This different modulation of components of the HLA class I antigen processing-presenting machinery results in a differential ability to present a CD8 + T cell epitope whose generation is dependent on the LMP7 immunoproteasome subunit. Conclusions: Overall, these findings establish that under conditions of persistent HCV antigenemia, HLA class I antigen processing and presentation are distinctively regulated during DC maturation. 2014 European Association for the Study of the Liver. Published

Chronic hepatitis B (CHB) is a complex disease with significant social impact both on the patients’ quality of life of and the economic resources involved. Its chronicity affects considerably not only the clinical management of the disease (for the need for drugs with proven long-term safety and low rate of resistance), but also the economic impact (for the high costs of treatment, the management of complications, and the constant monitoring of therapy).Since, as is well known, the main problem of modern health care systems is the general scarcity of available resources in the face of growing demand for health, the issue of economic evaluation of therapies for the treatment of chronic hepatitis B has been addressed in numerous national and international studies. In fact, clinicians find a strong support for the choice of the most suitable therapeutic pathway in the major scientific societies’ guidelines (European Association for the Study of The Liver – EASL, American Association for the Study of Liver Diseases – AASLD, Associazione Italiana per lo Studio del Fegato – AISF), while the analysis of the economic implications is rather more difficult, even for the methodological differences and peculiarities of the different countries.The aim of this paper is to present a brief summary of some of the recently conducted cost-effectiveness analyses and extrapolate some data to support the economic evidence related to the treatment of CHB with nucleos(t)ide analogs. In particular, the article focuses on the comparison between entecavir (ETV) and tenofovir (TDF), the two oral antiviral therapies recommended for first-line treatment. In the selected studies, the comparison between the different treatment options was conducted in order to assess the incremental cost-effectiveness ratio (ICER) and the results were expressed in terms of QALYs (Quality Adjusted Life Years) gained.Despite the methodological differences among the selected studies, tenofovir is found to be, in the context of first-line oral antiviral therapies, the most cost-effective treatment for patients with chronic hepatitis B.

Background & Aims In patients with chronic HCV-1 infection, recent evidences indicate that determination of a dinucleotide polymorphism (ss469415590, ΔG/TT) of a new gene, designated IFN λ-4, might be more accurate than the 12979860CC type of the IL28B locus in predicting sustained virological response (SVR) following peg-interferon and ribavirin. In addition, combined genotyping of different SNPs of the IL28B locus was shown to help dissect patients most prone to SVR among those with rs12979860CT. We examined whether single or combined genotyping of two IL28B SNPs, rs12979860 and rs8099917, and ss469415590 variation might improve the prediction of SVR. Results In the study cohort of 539 patients, 38% had SVR. The SNPs 12979860CC, rs8099917TT, and rs469415590TT/TT correlated significantly with SVR (68%, 50%, and 67%). Carriers of either the triplotype rs12979860CC_ss469415590TT/TT_rs8099917TT or the diplotype rs12979860CC_ss469415590TT/TT had the highest SVR rate (72%). In carriers of the rs12979860 T allele, neither the rs8099917 nor the ss469415590 improved the response prediction. After pooling this finding with data from previous studies, in rs12979860 T heterozygous individuals the co-presence of the rs8099917TT SNP was associated with improved response prediction. Conclusion In HCV-1 patients, the rs12979860 polymorphism appeared as the hit SNP better predicting response following peg-interferon and ribavirin treatment. Additional ss469415590 or rs8099917 genotyping had no added benefit for response prediction. In the subset of carriers of the rs12979860 T allele, genotyping of the rs8099917 SNP was unhelpful in the present investigation, but may inform clinical prediction of treatment response when our data were pooled with previous investigations.

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.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 DNA80 IU/ml.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 20 months (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), p0.001). 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 2000 IU/ml was not associated with the probability of disease progression (HR 0.20 (95% CI 0.03 to 1.10), p=0.10).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 2000 IU/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.

The combination of sofosbuvir and simeprevir ± ribavirin (SOF + SMV ± RBV) for hepatitis C virus (HCV) treatment has been associated with high rates of sustained virological response (SVR). Few data are available regarding this regimen in HIV/HCV co-infected patients. This study evaluated the effectiveness and safety of a 12-week course of SOF + SMV ± RBV in a cohort of HCV monoinfected and HIV/HCV co-infected individuals. HCV-infected patients, with or without HIV infection, receiving a 12-week course of SOF + SMV ± RBV in four Italian centres from February to October 2015, were included in this retrospective observational study. Clinical and biochemical data were retrieved for all patients. A total of 88 individuals were evaluated: 29 (33.0%) HIV/HCV co-infected and 59 (67.0%) monoinfected. Most patients were males with HCV genotype 1b (62.5%) and 1a (25%) infection. RBV was used in 41 HCV monoinfected and 6 HIV/HCV co-infected patients. Cirrhosis was found in 67 patients (76.1%). The most common adverse events (AEs) were rash and/or pruritus (23.9%), fatigue (13.6%) and anaemia (9.1%). Serious AEs occurred in three patients (3.4%). No treatment discontinuations were observed. RBV use was associated with multiple AEs (P = 0.02). An overall SVR12 of 93.2% was achieved; 96.6% in HCV monoinfected and 86.2% in HIV/HCV co-infected individuals, without significance both in univariate (P = 0.09) and multivariate analyses (P = 0.12). A baseline platelet count ≥90 000/mm3 was associated with higher rates of SVR (P = 0.005). A 12-week course of SOF + SMV ± RBV was associated with good safety and high SVR12 rate both in HCV monoinfected and HIV-HCV co-infected individuals.

Background and Aim Tenofovir disoproxil fumarate (TDF) is recommended as first-line monotherapy for nucleos(t)ide (NA)-naive chronic hepatitis B (CHB) patients and as a second-line rescue therapy for NA-experienced patients with a previous treatment failure. However, data regarding the efficacy of TDF monotherapy in patients with lamivudine resistance (LAM-R) successfully treated with LAM + adefovir (ADV) are limited. Herein, the efficacy and safety of switching from LAM + ADV to TDF monotherapy in clinical practice have been evaluated. Methods Sixty LAM-R HBeAg-negative CHB patients treated with ADV add-on therapy and stable viral suppression, were switched to TDF monotherapy and prospectively evaluated for virological response, liver and renal function, and bone mineral density. Results During a median period of 57 months of TDF monotherapy, all patients maintained a virological response, four of whom cleared HBsAg (6.6%) and discontinued treatment. Monitoring of renal function showed no case of the Fanconi syndrome, no significant alterations of median serum creatinine, eGFR and phosphate levels, although a reduction of TDF dosage was required in five patients (8.3%). Despite the stable virological suppression, five cirrhotic patients and one CHB patient developed hepatocellular carcinoma. Conclusions Our results demonstrate the efficacy of switching to TDF monotherapy in virologically suppressed CHB patients receiving long-term LAM + ADV therapy, with a low rate of adverse events.

Summary Background Therapy of chronic hepatitis D with Interferon is successful when testing for HDV-RNA turns negative. This end-point is disputed. Aim To assess the role of serum hepatitis B surface antigen (HBsAg) in the clearance of HDV-RNA in pegylated interferon (Peg-IFN)-treated chronic hepatitis D (CHD). Methods Sixty-two patients with CHD, treated with Peg-IFN, were considered. The patients belonged to three groups: 14 patients cleared the HBsAg and HDV-RNA (responders, R), 12 cleared the HDV-RNA remaining positive for HBsAg (partial responders, PR) and 36 cleared neither the HBsAg nor the HDV-RNA (nonresponders, NR). Results In responders, at baseline the median value (mv) of HBsAg and HDV-RNA was 1187 and 188 663 IU/mL. By month 6 of therapy, HBsAg declined to less than 1000 IU/mL and HDV-RNA was undetectable in 12 patients. In NR, the pre-therapy median value of HBsAg and HDV viremia was 6577 and 676 319 IU/mL. There was no significant reduction of antigen at month 6; after a decline, HDV-RNA rebounded to baseline levels. In PR, the median value of baseline HBsAg was 7031 IU/mL; it declined at month 6 in the majority. HDV-RNA progressively declined from an initial median value of 171 405 IU/mL. HBsAg

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.

direct anti-hepatitis B agents; however, prevalence and clinical impact of this adverse event are poorly appreciated. Material and Methods: 124 patients (78% males, 58 yr, 60% cirrhosis, 14% with 2(OH)-vitamin D deficiency, 90% under tenofovir±lamivudine treatment for 15 months) underwent two dual energy X-ray absorptiometry (DXA) of the lumbar spine (LS) and femoral neck (FN) performed at least 12 months a part. A T score of less than -2.5 and a T score between -1 and -2.5 identified osteoporosis and osteopenia, respectively (WHO criteria). All patients lacked concomitant medication affecting bone metabolism or osteoporosi in the first DXA scan. Results: During a median interval of 15 months (12-50) between DXA scan, 13 (26%) of 50 (40%) patients with normal BMD at the first DXA scan progressed to osteopenia (3 at LS, 7 at FN and 3 at both LS and FN) but none to osteoporosis. Among the 74 (60%) patients with osteopenia at the first DXA scan, 5 (7%) progressed to osteoporosis (2 at LS, 2 at FN and 1 at both LS and FN). Overall, 77% of the patients had stable BMD, 8% improved and 15% worsened. Median LS and FN T scores remained stable between DXA scans (-0.70 vs -0.80; -1.10 vs -1.10, p=ns). Age, gender, BMI, cirrhosis, nucleotide treatment, duration of antiviral therapy, immunosuppression and vitamin D status were not associated with worsening of BMD. In conclusion, in patients with chronic hepatitis B under nucleos(t)ide therapy, BMD worsened in a minority of patients only.

Aim: To evaluate similarities and differences in HCV-1 subtypes 1a and 1b in the presenting clinical features and the response to peg-interferon and ribavirin (Peg/RIBA).Patients and methods: A total of 1,233 naïve patients with HCV genotype-1 infection, 159 (13%) with subtype 1a and 1,074 (87%) with subtype 1b were treated with Peg-IFN/RIBA at 12 Italian centers. Covariates included in the logistic model were age, gender, BMI, serum alanine aminotransferase, serum gamma-glutamiltranspeptidase (γGT), platelets counts, liver fibrosis, the occurrence of type 2 diabetes, baseline viremia, and IL28B genotype.Results: At multivariate analysis, baseline characteristics differentiating patients with HCV-1a versus HCV-1b were young age, male gender, no F4 fibrosis, and no diabetes. SVR was achieved by 37% of patients with subtype 1b and 45% of those with subtype 1a, a nonsignificant difference of 8% (p=0.069). In patients with subtype 1a, predictors of SVR were IL28B CC (OR 5.78, CI 1.98–16.83), RVR (OR 4.18, CI 1.66–10.55), female gender (OR 2.83, CI 1.83–6.78), and HCVRNA (OR 0.55, CI 0.32–0.96). In patients with subtype 1b, the ranking of predictors was levels RVR (OR 6.49, CI 4.32–9.73), IL28B CC (OR 3.32, CI 2.15–4.58), γGT (OR 1.59, CI 0.14–2.22), HCVRNA (OR 0.61, CI 0.47–0.79), and age (OR 0.01, CI 0.02–0.42).Conclusion: In Italy HCV-1 subtype 1a prevails in young male patients with less advanced liver damage, findings that imply a more recent spreading of the infection with this viral strain. The two HCV-1 subtypes appear equally responsive to Peg-IFN/RIBA, with IL28B genotyping and monitoring of RVR mostly influencing the therapeutic response.

Objectives Nucleotide 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. Patients and methods We 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 m2. Results During 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 m2, 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. Conclusions In 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.

s / Digestive and Liver Disease 47S (2015) e1–e18 e13 escape the demonstration of arterial hypervascularity, CEUS must be performed immediately after conventional US to contrast the malignant fate of small lesions arising in cirrhotics. http://dx.doi.org/10.1016/j.dld.2015.01.030

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.

none 29 no Background: Aim was to select naïve patients with genotype 1 chronic hepatitis C having a high probability of response to Peg-interferon. +. ribavirin therapy. Methods: In 1073 patients (derivation cohort), predictors of rapid and sustained virological response were identified by logistic analysis; regression coefficients were used to generate prediction models for sustained virological response. Probabilities at baseline and treatment week 4 were utilized to develop a decision rule to select patients with high likelihood of response. The model was then validated in 423 patients (validation cohort). Results: In the derivation cohort, 257 achieved rapid virological response and 818 did not, with sustained virological response rates of 80.2% and 25.4%, respectively; interleukin-28B polymorphisms, fibrosis staging, gamma-glutamyl transferase, and viral load predicted sustained virological response. Assuming a

Introduction: Acute hepatitis C (AHC) is asymptomatic in about 70-80 % of cases and, therefore, is usually undiagnosed. Although the clinical course is typically mild, AHC has a high rate of transition to chronicity. Material and methods: We evaluated the literature data concerning risk factors for HCV transmission, diagnosis, natural history, and antiviral treatment of AHC. Results: Although new methods have been developed, anti-HCV seroconversion remains the gold standard for the diagnosis of AHC. This phenomenon, however, is identifiable in less than half of cases in the everyday clinical practice, since most AHC patients do not know their previous anti-HCV/HCV-RNA status. An early short-term interferon treatment in AHC patients prevents progression to chronicity in most of treated patients. Conclusion: The literature data give evidence of the clinical relevance of an early diagnosis of AHC for an early short-term interferon treatment. There is also the suggestion to use newly developed laboratory methods to distinguish AHC from an acute exacerbation of a chronic HCV infection. © 2014 Springer-Verlag.

Background Plasma homocysteine (Hcy) is an independent risk factor for cardiovascular disease. High levels of plasma Hcy have been observed in end-stage renal disease patients. Few studies have compared peritoneal dialysis (PD) and hemodialysis (HD) patients and few data are available on erythrocyte folate (ery-F) levels in dialysis patients. Objectives To evaluate plasma Hcy concentrations, vitamin B12 (B12), and folate status in dialysis patients; to analyze the possible causes of high Hcy levels; to follow up changes in folate and B12 concentrations after 6 months. Design A cross-sectional observational study. Setting Nephrology division and laboratory of hematology in a university and clinical research hospital. Patients The study included 82 patients treated with PD for 37 ± 37 months and 70 patients treated with HD for 136 ± 95 months. Laboratory Methods Plasma Hcy was measured by the immunoenzymatic IMx Hcy FPIA method (Abbott Laboratories, Diagnostic Division, Abbott Park, IL, U.S.A.), serum folate (s-F) and ery-F by the Stratus folate fluorometric enzyme-linked assay, and B12 by the Stratus vitamin B12 fluorometric enzyme-linked assay (DADE-Behring, Newark, DE, U.S.A.). Results Ninety-six percent of PD and 97% of HD patients had Hcy levels above the cutoff (13.5 μmol/L). Homocysteine level was higher in HD than in PD patients, while the prevalence of hyperhomocysteinemia was similar with the two techniques. Erythrocyte folate was significantly higher in PD (1333 ± 519 pmol/L) than in HD (1049 ± 511 pmol/L, p < 0.01). Statistically significant correlations were observed between Hcy and B12, s-F, ery-F, and dialysis duration. Multivariate analysis showed a strong correlation between s-F and Hcy. After 6 months there were no differences in Hcy, B12, s-F, and ery-F levels. Conclusions Plasma Hcy levels were high in more than 95% of our dialysis patients, with no relation to the type of dialysis. Vitamin B12 and folate were normal in the majority of our patients. However, serum folate was the major determinant of Hcy levels. Such a relation between Hcy and folate suggests that levels of folate within the reference interval are inadequate for dialysis patients.

An estimated 400 million people are chronically infected with hepatitis B virus (HBV), worldwide, and over 500,000 chronic hepatitis B (CHB) patients die annually because of cirrhosis and hepatocellular carcinoma (HCC) [1,2]. Clinical care for patients with CHB has advanced considerably during the last decades as a result of growing knowledge about the mechanisms of disease, diagnostic procedures and advances in therapeutic options.

Background The 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. Aims To evaluate the proportion of HBsAg-positive immigrants enrolled in this multicenter Societa` 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. Methods From February 1 to July 31 2008, anonymous data were obtained from all HBsAg-positive patients aged C18 years observed at 74 Italian centers of infectious diseases. Results Of the 3,760 HBsAg-positive subjects enrolled, 932 (24.8 %) were immigrants, with a prevalent distribution in central to northern Italy. The areas of origin were: Far East (37.1 %), Eastern Europe (35.4 %), Sub- Saharan Africa (17.5 %), North Africa (5.5 %), and 4.5 % from various other sites. Compared to Italian carriers, migrants were significantly younger (median age 34 vs. 52 years), predominantly female (57.5 vs. 31 %), and most often at first observation (incident cases 34.2 vs. 13.3 %). HBeAg-positives were more frequent among migrants (27.5 vs. 14 %). Genotype D, found in 87.8 % of Italian carriers, was present in only 40 % of migrants, who were more frequently inactive HBV carriers, with a lower prevalence of chronic hepatitis, cirrhosis, and hepatocellular carcinoma (HCC). Only 27.1 % of migrants received antiviral treatment compared to 50.3 % of Italians. Conclusions Twenty-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

Background & Aims In 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. Methods One hundred and ninety-one patients with chronic HBeAg-negative hepatitis B successfully treated with LAM monotherapy for at least 5years were included. Biochemical and virological tests were assessed every 3months in all patients and HBsAg quantification was performed in 45/191. Reverse-transcriptase (RT) region was directly sequenced in virological breakthrough patients. Results One hundred and ninety-one patients (148 males, median age 53years, 72 with compensated cirrhosis) responding to 60-month LAM monotherapy continued to receive LAM monotherapy beyond the initial 5years 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. Conclusions In 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.

s / Digestive and Liver Disease 47S (2015) e1–e18 e13 escape the demonstration of arterial hypervascularity, CEUS must be performed immediately after conventional US to contrast the malignant fate of small lesions arising in cirrhotics. http://dx.doi.org/10.1016/j.dld.2015.01.030