Abstract 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.

Abstract Therapy of acute hepatitis C (AHC) has not yet been standardized and several issues are still unresolved. This open, randomized, multicenter trial aimed to assess the efficacy and safety of a 24-week course of pegylated IFN (Peg-IFN) alpha-2b versus a 12-week course of Peg-IFN alpha-2b alone or with ribavirin (RBV) in AHC patients. One hundred and thirty HCV acutely infected patients who did not spontaneously resolve by week 12 after onset were consecutively enrolled and randomized to receive Peg-IFN alpha-2b monotherapy (1.5 μg/kg/week) for 24 or 12 weeks (arm 1, n = 44 and arm 2, n = 43, respectively) or in combination with RBV (10.6 mg/kg/day) for 12 weeks (arm 3, n = 43). The primary endpoint was undetectable HCV RNA at 6-month posttreatment follow-up (sustained virological response; SVR). All patients were followed for 48 weeks after therapy cessation. HCV RNA levels were determined by real-time polymerase chain reaction (limit of detection: 15 IU/mL) at the central laboratory at baseline, week 4, end of treatment, and 6 and 12 months posttreatment. Using an intent-to-treat analysis, overall SVR rate was 71.5%. In particular, an SVR was achieved in 31 of 44 (70.5%), 31 of 43 (72.1%), and 31 of 43 (72.1%) patients in arms 1, 2, and 3, respectively (P = 0.898). Sixteen patients (12.3%) prematurely discontinued therapy or were lost to follow-up; thus, sustained response rates with per-protocol analysis were 81.6%, 81.6%, and 81.6% for patients in arms 1, 2, and 3 respectively. With multivariate analysis, virologic response at week 4 of treatment was an independent predictor of SVR. Peg-IFN alpha-2b was well tolerated. CONCLUSION: Peg-IFN alpha-2b induces a high SVR in chronically evolving AHC patients. Response rates were not influenced by combination therapy or treatment duration.

Abstract 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.

ABSTRACT: 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.

Abstract 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<0.001). HCC incidence was higher in older patients (p<0.001) and patients with lower baseline platelet counts (p=0.02). Twelve patients who developed HCC achieved virologic response (HBV DNA <80 IU/mL) before HCC. At baseline, higher CU-HCC and GAG-HCC, but not REACH-B scores were associated with development of HCC. Discriminatory performance of HCC risk scores was low, with sensitivity ranging from 18% to 73%, and c-statistics from 0.71 to 0.85. Performance was further reduced in Caucasians with c-statistics from 0.54 to 0.74. Predicted risk of HCC based on risk-scores declined during ETV therapy (all p<0.001), but predictive performances after 1 year were comparable to those at baseline. CONCLUSIONS: Cumulative incidence of HCC is low in patients treated with ETV, but ETV does not eliminate the risk of HCC. Discriminatory performance of HCC risk scores was limited, particularly in Caucasians, at baseline and during therapy. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

BACKGROUND &#38; 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.

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.

Abstract PURPOSE: To develop recommendations for the management of acute hepatitis B by the Italian Society for the Study of Infectious and Tropical Diseases. METHODS: Development of the recommendations divided into three levels of evidence according to the GRADE system: A (high), B (medium) and C (low experts opinion), together with three recommendation levels: 1 (strong), 2 (medium), 3 (weak). RESULTS: The treatment with antivirals is in selected cases the mainstay of management of severe acute hepatitis, and should be started as a matter of urgency in order to prevent death. CONCLUSIONS: These recommendations are meant to provide the rationale and practical indications for the management of acute hepatitis B (AHB).

Abstract The efficacy data obtained with boceprevir and telaprevir for persons with hepatitis C virus (HCV) genotype 1 infection raise the question of whether HCV protease inhibitors should be used in human immunodeficiency virus (HIV)/HCV co-infected persons. The Italian Association for the Study of Infectious and Tropical Diseases has made these recommendations to provide the rationale and practical indications for the use of triple anti-HCV therapy in persons living with HIV (PLWHIV). A Writing Committee of experts indicated by the President of the Association and a Consulting Committee con- tributed to the document. The final draft was submitted to the evaluation of external experts and the text modified according to their suggestions and comments. Treatment of HCV co-infection should be considered for all HCV RNA positive PLWHIV. Response-guided therapy with pegylated interferon and ribavirin is the standard treatment of PLWHIV with infection by HCV genotype 2, 3, 4, 5 and 6. Boceprevir and telaprevir should be used to treat HCV genotype 1 infection in HIV/HCV co-infected patients for 48 weeks on an individual basis, with close monitoring of their efficacy and tolerability with concur- rent antiretroviral therapy, taking into account potential drug-drug interactions. The decision to treat a patient or to wait for better treatment options, or to discontinue treatment should be made on an individual basis taking into account pre-treatment variables and the on-treatment HCV RNA kinetics.

The Italian recommendations for the therapy of hepatitis B virus (HBV)-related disease were issued in 2008. Subsequently in 2008 the nucleotide analogue (NA) Tenofovir was approved for antiviral treatment. The introduction of this important new drug has called for the current guidelines update, which includes some additional revisions: (a) the indication for therapy is extended to mild liver fibrosis and the indication for treatment is graded as “possible”, “optional” or “mandatory” according to the fibrosis stage; (b) two different treatment strategies are described: first line definite duration treatment with interferon, long-term treatment of indefinite duration with NA; (c) the indication to follow either strategy is also based on the stage of liver fibrosis; (d) virological monitoring is modified to include the definitions of failure and of sustained virological response to interferon therapy; (e) the recommendation to use HBV DNA assays with high sensitivity and wide linear ranges is underlined (f) guidelines on post-treatment follow-up after finite treatment with NA, potential side effects of therapy and non-virological monitoring are defined; (g) definitions and treatment of patients without optimal response to NA are reported; (f) treatment and monitoring of compensated or decompensated cirrhosis and hepatocellular carcinoma are updated.