Hepatitis: Mangia A

Puoti C, Guido M, Mangia A, Persico M, Prati D, Anonymous00025. · Department of Gastroenterology and Internal Medicine, E. De Santis Hospital, Via A. Grandi 43, 00045 Genzano, Rome, Italy. · Dig Liver Dis. · Pubmed #12846410 No free full text.

Abstract: An ad hoc committee appointed by the Italian Association for the Study of the Liver (AISF) proposed these Practice Guidelines for the management of HCV carriers with persistently normal aminotransferase levels. Only stringent ALT determinations will make it possible to distinguish these subjects from those in temporary biochemical remission. The overall prevalence in Italy has been estimated between 1.5 and 10.6%. HCV RNA quantitation and genotype determination are not predictors of the presence and severity of liver damage nor correlate with the outcome of the disease, and should not be used in clinical practice for the management and surveillance of HCV carriers with normal ALT. Only a minority of HCV carriers with normal ALT levels show a normal morphological picture (true 'healthy carriers'). Disease activity is mild in most cases; fibrosis is generally mild and cirrhosis is very rare. Histological activity, as monitored by sequential liver biopsies, seems to have very slow evolution. HCV carriers should not undergo liver biopsy on a routine basis. Liver biopsy can be reasonably proposed only in selected cases. Until the results of studies with PEG interferon plus ribavirin are available, HCV carriers should not receive antiviral treatment outside controlled experimental studies.

Andriulli A, Mangia A, Iacobellis A, Ippolito A, Leandro G, Zeuzem S. · Division of Gastroenterology, Casa Sollievo della Sofferenza Hospital, IRCCS, San Giovanni Rotondo, Italy. · Aliment Pharmacol Ther. · Pubmed #18549461 No free full text.

Abstract: BACKGROUND: Anti-viral therapy seems more successful in HCV genotype 2 than genotype 3-infected patients. AIM: To report sustained virological response (SVR) rates for HCV-2 and HCV-3 infection. METHODS: Meta-analyses were carried out on SVR data on 2275 patients treated for 24 weeks in eight individual trials and on 968 patients with rapid virological response (RVR) treated for 12-16 weeks or 24 weeks in four studies. RESULTS: After 24 weeks of therapy, SVR rates were 74% and 68%, respectively, for HCV-2 and HCV-3 genotype patients. Among high viraemics, SVR rate in HCV-2 infection (75%) differed from the 58% value in HCV-3 infection. Among low viraemic patients, respective rates were 79% and 75%. In RVR patients treated for 12-16 or 24 weeks, SVR rates in HCV-2 infection were 83% and 84%, respectively, and in HCV-3 infection 84% and 86%. In patients without RVR treated for 24 weeks, SVR was higher in HCV-2, with a 17.8% weighted difference. CONCLUSIONS: Twenty-four weeks of therapy should remain standard duration for HCV-2 and low viraemic HCV-3 patients. In RVR patients, HCV-3 patients respond to short-treatment as well as HCV-2 patients, irrespective of basal viraemia. Patients without RVR may need longer treatment than the recommended 24 weeks.

Mangia A, Burra P, Ciancio A, Fagiuoli S, Guido M, Picciotto A, Fabrizi F, Anonymous00319. · Division of Gastroenterology, General Hospital, IRCCS, San Giovanni Rotondo - Italy. · Int J Artif Organs. · Pubmed #18286451 No free full text.

Abstract: The management of hepatitis C virus (HCV)-infected patients with chronic kidney disease (CKD) is complex and represents a particular concern since numerous issues, such as antiviral therapy in dialysis patients and post renal transplant, and prevention of HCV spread within dialysis units, remain unresolved. An enormous body of literature has been published on HCV in the CKD population; however, clinical evidence on important issues is mostly based on uncontrolled clinical trials or retrospective surveys. The aim of this paper is to provide a systematic review of the literature. Responses to the critical issues have been developed by a consensus of experts, endorsed by the Italian Association for the Study of the Liver (AISF) and some clinical recommendations have been added.

Marzano A, Angelucci E, Andreone P, Brunetto M, Bruno R, Burra P, Caraceni P, Daniele B, Di Marco V, Fabrizi F, Fagiuoli S, Grossi P, Lampertico P, Meliconi R, Mangia A, Puoti M, Raimondo G, Smedile A, Anonymous00107. · Division of Gastroenterology and Hepatology, AO San Giovanni Battista, Torino, Italy. · Dig Liver Dis. · Pubmed #17382608 No free full text.

Abstract: The literature on hepatitis B virus (HBV) in immunocompromised patients is heterogeneous and referred mainly to the pre-antivirals era. Today a rational approach to the problem of hepatitis B in these patients provides for: (a) the evaluation of HBV markers and of liver condition in all subjects starting immunosuppressive therapies (baseline), (b) the treatment with antivirals (therapy) of active carriers, (c) the pre-emptive use of antivirals (prophylaxis) in inactive carriers, especially if they are undergoing immunosuppressive therapies judged to be at high risk, (d) the biochemical and hepatitis B surface antigen (HBsAg) monitoring (or universal prophylaxis, in case of high risk immunosuppression) in subjects with markers of previous contact with HBV (HBsAg negative and anti-HBc positive), in order to prevent reverse seroconversion. Moreover it is suggested a strict adherence to criteria of allocation based on the virological characteristics of both recipients and donors in the general setting of transplants and in liver transplantation the universal prophylaxis with nucleos(t)ides analogues (frequently combined with specific anti-HBV immunoglobulins) in HBsAg positive candidates and in HBsAg negative recipients of anti-HBc positive grafts.

Mangia A. · Division of Gastroenterology, Hospital Casa Sollievo della Sofferenza, IRCCS, San Giovanni Rotondo, Italy. · J Viral Hepat. · Pubmed #17381713 No free full text.

Abstract: Peginterferon alpha (PegIFN alpha) plus ribavirin achieves sustained virological response (SVR) in more than 50% of patients with chronic hepatitis C virus (HCV) infection. Although in the trials which led to the registration of this combination therapy, only a 48-week period of treatment had been evaluated, current international guidelines state that 48 or 24 weeks of treatment should be recommended in accordance with genotype; i.e. 48 weeks for genotypes 1 and 4, and 24 weeks for 2 and 3. However, side effects and the high cost of antiviral therapy forced investigators to evaluate further reductions in the treatment duration. Based on the new evidence that fast and persistent viral clearance is highly predictive of SVR, a week 4 negative HCV RNA by a sensitive molecular assay was recently utilized as a criterion for halving the duration of treatment to 12-16 weeks for genotypes 2 and 3, and 24 weeks for genotype 1 patients. However, some issues on this topic, are still open. In this review, existing evidence is discussed, and both the relevance and limitations of published studies are considered.

Dalgard O, Mangia A. · Department of Microbiology Ullevål University Hospital, Oslo, Norway. · Drugs. · Pubmed #17040112 No free full text.

Abstract: In the past 10 years, progress has been made in the management of patients with chronic hepatitis C. A sustained virological response (SVR) is achieved in 80-85% of patients infected with hepatitis C virus (HCV) genotype 2 or 3 after 24 weeks of treatment with peginterferon-alpha and ribavirin. Treatment durations <24 weeks have been investigated to determine whether shorter-term therapy reduces adverse effects and costs compared with longer-term therapy without compromising efficacy. Three studies involving only patients with HCV genotype 2 or 3, with different baseline patient characteristics have shown that 12-16 weeks of treatment can be as effective as 24 weeks of treatment. In all three trials, undetectable HCV RNA 4 weeks after the start of treatment was defined as rapid virological response (RVR), and only patients with RVR stopped treatment early.In the first trial, 75% of patients treated with peginterferon-alpha-2b and ribavirin achieved RVR; these rapid responders achieved an SVR rate of 90% after 14 weeks of treatment. In the second trial, 63% of patients achieved RVR after 4 weeks of treatment with peginterferon-alpha-2b and ribavirin, and 85% of patients with RVR achieved SVR after 12 weeks of treatment. In comparison, 91% of patients with RVR treated for 24 weeks had SVR. In the third study, 93% of the total study population achieved RVR and were randomly assigned to 16 or 24 weeks of treatment with peginterferon-alpha-2a and ribavirin. Among patients with RVR, 85% in the group treated for 16 weeks and 80% in the group treated for 24 weeks achieved SVR. Among patients with HCV genotype 2 or 3, achieving an RVR to interferon-based treatment is common and a criterion to reduce the duration of treatment. In patients with genotype 2 and RVR, 12 weeks of therapy with peginterferon-alpha and ribavirin is recommended. For patients with genotype 3, a univocal recommendation on treatment duration cannot be made. However, ongoing trials will probably clarify this aspect.

Mangia A, Santoro R, Minerva N, Ricci GL, Carretta V, Persico M, Vinelli F, Scotto G, Bacca D, Annese M, Romano M, Zechini F, Sogari F, Spirito F, Andriulli A. · Gastroenterology Unit, IRCCS Casa Sollievo della Sofferenza Hospital, San Giovanni Rotondo, Italy. · N Engl J Med. · Pubmed #15972867 links to  free full text

Abstract: BACKGROUND: We hypothesized that in patients with hepatitis C virus (HCV) genotype 2 or 3 in whom HCV RNA is not detectable after 4 weeks of therapy, 12 weeks of treatment is as effective as 24 weeks. METHODS: A total of 283 patients were randomly assigned to a standard 24-week regimen of peginterferon alfa-2b at a dose of 1.0 mug per kilogram weekly plus ribavirin at a dose of 1000 mg or 1200 mg daily, on the basis of body weight. Of these, 70 patients were assigned to the 24-week regimen (standard-duration group) and 213 patients to a variable regimen (variable-duration group) of 12 or 24 weeks, depending on whether tests for HCV RNA were negative or positive at week 4. The primary end point was HCV that was not detectable by polymerase-chain-reaction (PCR) assay 24 weeks after the completion of therapy. RESULTS: In the standard-duration group, 45 (64 percent) patients had HCV that was not detectable by PCR assay at week 4, as compared with 133 (62 percent) in the variable-duration group (difference [the rate in the standard-duration group minus that in the variable-duration group], 2 percent; 95 percent confidence interval, -11 to 15 percent). Fifty-three patients (76 percent) in the standard-duration group and 164 patients (77 percent) in the variable-duration group had a sustained virologic response (difference, -1 percent; 95 percent confidence interval, -13 to 10 percent). Fewer patients in the variable-duration group receiving the 12-week regimen had adverse events and withdrew than in the group receiving the 24-week regimen (P=0.045). The rate of relapse (defined as HCV not detectable at the end of treatment but detectable at the end of follow-up) was 3.6 percent in the standard-duration group and 8.9 percent in the variable-duration group (P=0.16). Overall, the rate of sustained virologic response was 80 percent among patients with HCV genotype 2 and 66 percent among those with genotype 3 (P<0.001). CONCLUSIONS: A shorter course of therapy over 12 weeks with peginterferon alfa-2b and ribavirin is as effective as a 24-week course for patients with HCV genotype 2 or 3 who have a response to treatment at 4 weeks.

Mangia A, Ricci GL, Persico M, Minerva N, Carretta V, Bacca D, Cela M, Piattelli M, Annese M, Maio G, Conte D, Guadagnino V, Pazienza V, Festi D, Spirito F, Andriulli A. · Division of Gastroenterology, Casa Sollievo della Sofferenza Hospital, IRCCS, 71013 San Giovanni Rotondo, Italy. · J Viral Hepat. · Pubmed #15850470 No free full text.

Abstract: We determined whether triple therapy comprising amantadine (AMA), ribavirin (RBV) and either peginterferon (PEG-IFN) alpha-2a or conventional IFN alpha-2a would improve sustained virological response (SVR) rates over dual therapy with IFN alpha-2a and RBV in patients with chronic HCV infection. A total of 362 treatment-naïve patients were randomized to 48 weeks of treatment with: PEG-IFN alpha-2a 180 microg/week (group A) or IFN alpha-2a 3 MU tiw (groups B and C). All patients received RBV 1000 or 1200 mg/day and those in groups A and B received AMA 200 mg/day. SVR was defined as an undetectable HCV RNA after 24 weeks of untreated follow-up. At the end of therapy, 74.4% (95% CI 0.66-0.82) of patients in group A were HCV RNA-negative compared with 42.5% (95% CI 0.33-0.50) of those in group B (P = 0.0001) and 48.8% (95% CI 0.40-0.56) of those in group C. SVR was achieved in a significantly greater proportion of patients in group A compared with groups B and C: 65.3% (95% CI 0.53-0.56), 33.3% (95% CI 0.25-0.41) and 44.6% (95% CI 0.36-0.53; P = 0.0001) respectively. In patients with genotype 1, SVR rates were 55.2, 22.8 and 28.8% with the three regimens respectively. Factors independently associated with SVR were HCV genotype 2 or 3, therapy with PEG-IFN, female gender and age. In treatment-naive patients with chronic hepatitis C, triple therapy with PEG-IFN alpha-2a, RBV and AMA produces higher SVR than dual or triple therapy with conventional IFN alpha-2a.

Andriulli A, Persico M, Iacobellis A, Maio G, Di Salvo D, Spadaccini A, Bacca D, Leandro G, Ventrella F, Mangia A. · Division of Gastroenterology, Hospital Casa Sollievo della Sofferenza, IRCCS, San Giovanni Rotondo, Italy. · J Viral Hepat. · Pubmed #15500554 No free full text.

Abstract: Expert consensus recommends liver biopsy before therapy for chronic hepatitis C. A cost effectiveness analysis suggested that the best strategy in the management of patients was to treat without biopsy. We compared therapy in patients who did, or did not undergo biopsy. Hepatitis C virus (HCV)-positive patients (78) who did not agree to (n = 57) or with contraindications to liver biopsy (n = 21) (group A) were matched for age, sex and genotype with those who consented (group B). Before therapy (interferon/ribavirin for 12 months), a clinical diagnosis of chronic hepatitis, on the basis of standard biochemical and ultrasonographic parameters. The two groups showed similar baseline characteristics. A noninvasive, diagnosis of chronic hepatitis was made in 75.6% of group A, and in 83.3% of group B (P = 0.26). Concordance between clinical and histological diagnosis in group B amounted to 91%. End-of-therapy virological response was 52.6% in group A, and 57.7% in group B (P = 0.63). Sustained virological response was 41.0% [95% confidence interval (CI) 30.1-51.9] and 43.6% (95% CI 32.6-54.6) in the two groups (P = 0.87). Predictors of sustained response were noninvasive diagnosis of chronic hepatitis (P = 0.006), lack of portal hypertension (P = 0.037), platelets >10(5)/mm3 (P = 0.007), prothrombin >70% (P = 0.02), and genotype 2 or 3 (P < 0.0001). At multivariate analysis, genotype (P < 0.0001) and platelets (P = 0.004) maintained their predictive power. In most patients with HCV infection, virological clearance after therapy can be achieved irrespective of whatever a liver biopsy might show.

Mangia A, Spinzi G, Vuturo O, Pazienza V, Iacobellis A, Piattelli M, Giacobbe A, Leandro G, Piermanni V, Minoli G, Montalto G, Andriulli A. · Division of Gastroenterology, 'Casa Sollievo della Sofferenza' Hospital, IRCCS, S. Giovanni Rotondo, Italy. · Aliment Pharmacol Ther. · Pubmed #14984380 links to  free full text

Abstract: BACKGROUND: In patients with chronic hepatitis C virus infection and persistently normal alanine aminotransferase levels, liver fibrosis has been reported in 0-22% of cases and advanced liver disease in 5-10% of cases. AIM: To determine whether patients with persistently normal alanine aminotransferase levels clear infection after anti-viral therapy at equal or different rates from infected patients with raised alanine aminotransferase levels. METHODS: Thirty-five hepatitis C virus RNA-positive patients with fibrosis at liver histology (Group 1) were matched for genotype, sex, age and histology with patients with raised alanine aminotransferase levels (Group 2). Both groups were treated with 3 MU interferon-alpha2b plus ribavirin (1000-1200 mg) for 12 months. RESULTS: End-of-therapy response was achieved in 71.4%[95% confidence interval (CI), 56.4-86.3] of patients in Group 1 and in 52.3% (95% CI, 42.8-61.9) of those in Group 2 (P = 0.04). At week 72, 22 patients (62.8%; 95% CI, 46.8-78.1) in Group 1 and 50 patients (47.5%; 95% CI, 38.0-57.1) in Group 2 showed a sustained virological response (P = 0.11). Non-1 genotype was the only independent predictor of sustained response (P = 0.002), with an odds ratio of 3.45 (95% CI, 1.58-7.50). At month 3 of therapy, the positive predictive values for non-response were 100% and 96% in Groups 1 and 2, respectively. CONCLUSIONS: Interferon and ribavirin induce comparable sustained virological response in patients with persistently normal or raised alanine aminotransferase levels. Stage 1 fibrosis, rather than alanine aminotransferase levels, may be the criterion on which to decide whether or not to treat patients with persistently normal alanine aminotransferase levels.

Mangia A, Santoro R, Piattelli M, Leandro G, Minerva N, Annese M, Bacca D, Spirito F, Carretta V, Ventrella F, Cela M, Andriulli A. · Division of Gastroenterology, Ospedale Casa Sollievo della Sofferenza, IRCCS, San Giovanni Rotondo, Italy. · J Hepatol. · Pubmed #12076869 No free full text.

Abstract: BACKGROUND/AIMS: The aim of the present, open-labelled, controlled study was to determine whether 5 MU of interferon (IFN) alpha 2b combined with a standard dose of ribavirin might increase the rate of viral clearance in all patients with chronic HCV hepatitis or at least in those with an unfavourable genotype. METHODS: A total of 298 previously untreated patients with chronic hepatitis C were randomized to 5 or 3 MU of interferon alpha 2b 3 times per week with 1000-1200 mg of ribavirin daily (148 and 150 patients, respectively). Patients were treated for 12 months and observed for 6 months posttreatment. RESULTS: In patients infected with HCV genotype 1, the sustained virologic response was 37.8% (95% CI 27.3-48.1) with IFN 5 MU and 19.2% (95% CI 10.1-28.2) with IFN 3 MU (P=0.008). Out of 45 sustained responders with genotype 1, 31 (69%) had received 5 MU and 14 (31.1%) the standard 3 MU dose of IFN in combination with ribavirin (P=0.01). Of the 86 responders infected with genotype non-1, 39 (45.3%) were from the 5 MU IFN group and 47 (54.6%) were from the 3 MU IFN group; these figures were not significant. At the multivariate analysis of baseline features for all patients, the variables with an independent effect for a sustained response were genotype non-1 (odds ratio (OR) 3.98, 95% CI 2.36-6.40), and the histological grading (score 0-2) (OR 2.48, 95% CI 1.12-5.51) and staging (score 0-1) (OR 1.73, 95% CI 1.02-2.95). For patients with genotype 1 only the high regimen of IFN entered the model (OR 2.39, 95% CI 1.13-5.05), whereas for patients with genotype non-1 an age of <40 years (OR 2.64, 95% CI 1.23-5.70) and staging (score 0-1) (OR 2.38, 95% CI 1.07-5.28) were independent predictors of a sustained response. CONCLUSIONS: Our study suggests that when treating naive patients with genotype 1, there is a significant increase in the rate of sustained virologic clearance by increasing the dose of IFN given in combination with ribavirin.

Mangia A, Minerva N, Annese M, Leandro G, Villani MR, Santoro R, Carretta V, Bacca D, Giangaspero A, Bisceglia M, Ventrella F, Dell'Erba G, Andriulli A. · Division of Gastroenterology and Department of Human Pathology, Ospedale "Casa Sollievo della Sofferenza," IRCCS, San Giovanni Rotondo, Ospedale Canosa, Italy. · Hepatology. · Pubmed #11283865 No free full text.

Abstract: The aim of this study was to compare, in an open-label study, the efficacy and safety of a combination of interferon (IFN) and amantadine (AMA) with that of IFN alone in previously untreated patients with chronic hepatitis C. A total of 200 patients were randomized to 6 MU of IFN-alpha2a 3 times per week, with 200 mg of AMA daily (n = 99) or to an identical dose of interferon alpha2a (n = 101). Patients were treated for 12 months and observed for 6 months' posttreatment. At the completion of treatment, 28.7% of patients in the monotherapy group and 45.5% in the combination group had a virologic response (P =.014). At 6 months' posttreatment, a sustained virologic response was observed in 16.8% (95% CI: 9-23) of patients with IFN alone versus 29.3% (95% CI: 19-37) of patients who were treated with combination therapy (P =.036). In each of the 2 treatments, genotype was the only predictive parameter for a sustained response. At the logistic regression analysis, therapy and genotype were the only 2 parameters with an independent predictive value. In the combination group, at examination of month 3, hepatitis C virus (HCV)-RNA status had a 97.6% (95% CI: 93-102) positive predictive value and a 50% (95% CI: 37-63) negative predictive value for a sustained virologic clearance. A substantial proportion of naïve patients with chronic hepatitis C have an end-of-treatment and end-of-follow-up virologic and biochemical response to a combination of IFN and AMA. This new treatment appears safe and well tolerated.

De Compadri P, Koleva D, Mangia A, Motterlini Stat Sci N, Garattini L. · CESAV, Centre for Health Economics, 'Mario Negri', Institute for Pharmacological Research, 24020, Ranica, (BG), Italy. · J Med Econ. · Pubmed #19450116 No free full text.

Abstract: BACKGROUND: Pegylated interferon and ribavirin are at present the standard treatment for chronic hepatitis C virus (HCV) patients. OBJECTIVE: The present economic evaluation compared 12 vs. 24 weeks of peginterferon alfa-2b + ribavirin treatments for HCV genotypes 2 or 3. Shortening the period of antiviral therapy is important in terms of adverse events and costs. METHODS: Clinical evidence was based on the results of a multicentre, randomised controlled clinical trial (RCCT) conducted in Italy, which found that the shorter course of therapy was as effective as the 24-week course for patients with HCV genotypes 2 or 3 responding to treatment at 4 weeks. A cost minimisation analysis was performed. The analysis took the Italian National Health Service (INHS) point of view, thus only healthcare costs (drugs, medical consultations, diagnostic tests, hospital admissions) were considered. Healthcare activities were estimated by the RCCT principal investigators and were priced by applying the INHS tariffs and prices. RESULTS: The total mean cost per patient was estimated at euro9,785 for the standard group and euro7,508 for the variable-duration group. Sensitivity analysis confirmed the robustness of the baseline results. CONCLUSIONS: This study showed that the variable-duration regimen can be recommended as an efficient use of resources for patients from the INHS perspective.

Sebastiani G, Halfon P, Castera L, Pol S, Thomas DL, Mangia A, Di Marco V, Pirisi M, Voiculescu M, Guido M, Bourliere M, Noventa F, Alberti A. · Venetian Institute of Molecular Medicine, Padova, Italy. · Hepatology. · Pubmed #19291784 No free full text.

Abstract: The staging of liver fibrosis is pivotal for defining the prognosis and indications for therapy in hepatitis C. Although liver biopsy remains the gold standard, several noninvasive methods are under evaluation for clinical use. The aim of this study was to validate the recently described sequential algorithm for fibrosis evaluation (SAFE) biopsy, which detects significant fibrosis (> or =F2 by METAVIR) and cirrhosis (F4) by combining the AST-to-platelet ratio index and Fibrotest-Fibrosure, thereby limiting liver biopsy to cases not adequately classifiable by noninvasive markers. Hepatitis C virus (HCV) patients (2035) were enrolled in nine locations in Europe and the United States. The diagnostic accuracy of SAFE biopsy versus histology, which is the gold standard, was investigated. The reduction in the need for liver biopsies achieved with SAFE biopsy was also assessed. SAFE biopsy identified significant fibrosis with 90.1% accuracy (area under the receiver operating characteristic curve = 0.89; 95% confidence interval, 0.87-0.90) and reduced by 46.5% the number of liver biopsies needed. SAFE biopsy had 92.5% accuracy (area under the receiver operating characteristic curve = 0.92; 95% confidence interval, 0.89-0.94) for the detection of cirrhosis, obviating 81.5% of liver biopsies. A third algorithm identified significant fibrosis and cirrhosis simultaneously with high accuracy and a 36% reduction in the need for liver biopsy. The patient's age and body mass index influenced the performance of SAFE biopsy, which was improved with adjusted Fibrotest-Fibrosure cutoffs. Two hundred two cases (9.9%) had discordant results for significant fibrosis with SAFE biopsy versus histology, whereas 153 cases (7.5%) were discordant for cirrhosis detection; 71 of the former cases and 56 of the latter cases had a Fibroscan measurement within 2 months of histological evaluation. Fibroscan confirmed SAFE biopsy findings in 83.1% and 75%, respectively. CONCLUSION: SAFE biopsy is a rational and validated method for staging liver fibrosis in hepatitis C with a marked reduction in the need for liver biopsy. It is an attractive tool for large-scale screening of HCV carriers.

Mangia A, Minerva N, Bacca D, Cozzolongo R, Agostinacchio E, Sogari F, Scotto G, Vinelli F, Ricci GL, Romano M, Carretta V, Petruzzellis D, Andriulli A. · Liver Unit, IRCCS Casa Sollievo della Sofferenza, San Giovanni, Rotondo, Italy. · Hepatology. · Pubmed #19072829 No free full text.

Abstract: In hepatitis C virus (HCV) genotypes 2 and 3 patients, the high rate of relapse after 12 to 16 weeks of antiviral therapy is the main concern for shortening treatment duration. This study was undertaken to delineate predictors of relapse after short treatment in patients with undetectable HCV RNA at treatment week 4 (RVR), and to report in RVR patients with relapse the sustained virological response (SVR) after a second 24-week course of therapy. RVR patients received pegylated interferon (Peg-IFN) alfa-2b (1.5 microg/kg) and ribavirin (1000-1200 mg/day) for 12 weeks; those who relapsed were re-treated with the same drug doses but for the extended standard duration of 24 weeks. Logistic regression analysis was applied to delineate predictors of relapse by using age, sex, route of transmission, body mass index (BMI), serum alanine aminotransferase (ALT), HCV genotypes, serum HCV RNA levels, and platelet counts as covariates. Of 718 patients with genotypes 2 and 3 who were started on therapy, 496 (69.1%) had undetectable HCV RNA at week 4. Of them, 409 patients (82.5%, CI 79.1-85.8) attained SVR, and 67 (14.1%, CI 10.4-16.5) relapsed. At regression analysis, only platelet count less than 140,000 mm(3) [odds ratio, 2.51; confidence interval (CI), 1.49-4.20] and BMI 30 or higher (odds ratio, 1.7; CI, 1.03-2.70) were independently associated with relapse. Forty-three of 67 patients with relapse agreed to be re-treated, and an SVR was achieved in 30 (70.0%) of them. Conclusion: We recommend 12 weeks course of therapy for patients with undetectable HCV RNA at treatment week 4, providing they present with no advanced fibrosis and low BMI.

Pazienza V, Clément S, Pugnale P, Conzelmann S, Pascarella S, Mangia A, Negro F. · Division of Clinical Pathology, University Hospitals and University of Geneva, Geneva, Switzerland. · Liver Int. · Pubmed #18803589 No free full text.

Abstract: BACKGROUND: The liver disease expression in chronic hepatitis C patients is variable and may partially depend on the sequence of the infecting viral genotype. AIM: To identify some hepatitis C virus (HCV) genotype-specific virus-host interactions potentially leading to clinically significant consequences. METHODS: We compared the gene expression profile of Huh-7 cells transiently expressing the core protein of HCV genotype 1b and 3a using microarray technology. RESULTS: Thirty-two genes were overexpressed in Huh-7 transfected with the HCV genotype 1b core protein and 57 genes in cells transfected with the genotype 3a core protein. On the other hand, we found 20 genes downregulated by core 1b and 31 genes by core 3a. These included genes involved in lipid transport and metabolism, cell cycle, immune response and insulin signalling. CONCLUSION: The expression of HCV core proteins of different genotypes leads to a specific gene expression profile. This may account for the variable disease expression associated with HCV infection.

Andriulli A, Cursaro C, Cozzolongo R, Iacobellis A, Valvano MR, Mangia A, Minerva N, Bacca D, Stanzione M, Scuteri A, Montalto G, Andreone P. · Gastroenterology Unit, Casa Sollievo della Sofferenza Hospital, San Giovanni Rotondo, Italy. · J Viral Hepat. · Pubmed #18761603 No free full text.

Abstract: Guidelines for the treatment of patients infected with hepatitis C virus of genotypes 2 and 3 (HCV-2 and HCV-3, respectively) recommend a 24-week course of Peg-interferon (Peg-IFN) alpha-2a combined with ribavirin, despite 50% of patients in registration trials attaining a sustained virologic response (SVR) following Peg-IFN alpha-2a monotherapy. The aim of this study was to delineate patient characteristics that might help to identify individuals likely to benefit from ribavirin discontinuation. One hundred and forty-four HCV-2- and HCV-3-infected patients initiated Peg-IFN alpha-2a (180 microg/week) and ribavirin (1000 or 1200 mg/day); those with viral clearance at week 4 were randomized to either Peg-IFN alpha-2a monotherapy (n = 59) or continuing combination therapy (n = 61) until week 12. Overall, all but one patient with a rapid virologic response (RVR) responded by the end of therapy and the overall SVR rates were lower after discontinuation of ribavirin (54%vs 82%; P < 0.001). In RVR patients who discontinued ribavirin, low baseline viraemia helped predict SVR (odds ratio 11.2, 95% CI 2.7-47.1). SVR rates were similar in patients receiving mono- or combination therapy with low (< or =300,000 IU/mL) and intermediate viraemia (86%vs 81% and 70%vs 71%, 86% refers to low viraemic patients receiving monotherapy and 81% to those receiving combination therapy. Similarly, 70% refers to patients with intermediate viraemic levels receiving monotherapy and 71% to those receiving combination therapy), but different in those with high (>700,000 IU/mL) viraemia (37%vs 88%; P = 0.004). Thus in HCV-2- and HCV-3-infected patients, withdrawal of ribavirin and continuation of Peg-IFN alpha-2a monotherapy may be appropriate to attain an SVR, providing viraemia is cleared early during therapy and associated with low baseline viral load. These results warrant future investigations, as discontinuing ribavirin could lead to considerable savings in cost and quality of life related to over-treatment.

Stroffolini T, Almasio PL, Persico M, Bollani S, Benvegnù L, Di Costanzo G, Pastore G, Aghemo A, Stornaiuolo G, Mangia A, Andreone P, Stanzione M, Mazzella G, Saracco G, Del Poggio P, Bruno S, Anonymous00079. · Department of Gastroenterology, Ospedale San Giacomo, Roma, Italy. · Am J Gastroenterol. · Pubmed #18637087 No free full text.

Abstract: BACKGROUND: While the likelihood of developing hepatocellular carcinoma (HCC) in patients coinfected with both HBV and HCV is increased, the role of previous exposure to HBV as a risk factor associated with tumor occurrence in subjects with HCV-related cirrhosis has not been fully investigated. AIM: To assess whether serum anti-HBc positivity, as a marker of previous HBV exposure, is associated with HCC development in HCV-related positive, hepatitis B surface antigen (HBsAg) negative patients with cirrhosis treated with alfa-interferon (IFN) monotherapy. PATIENTS AND: A database including 883 consecutive patients (557 men, mean age 54.7 yr) with histologically METHODS: proven cirrhosis treated with IFN between 1992 and 1997 was analyzed. All subjects have been surveilled every 6 months by ultrasound. Independent predictors of HCC were assessed by Cox multiple regression analysis. RESULTS: Mean follow-up was 96.1 months. Anti-HBc testing was available in 693 cases and, among them, 303 patients (43.7%) were anti-HBc seropositive. Anti-HBc positive patients were more often men (67.0%vs 58.7%, P= 0.03), had lower transaminase levels (3.3 +/- 2.0 vs 3.8 +/- 2.5 u.l.n., P= 0.004), and had higher rate of alcohol intake (38.3%vs 22.5%, P < 0.001) than anti-HBc negative patients. Overall, the incidence rates of HCC per 100 person-years were 1.84 (95% CI 1.34-2.47) in the anti-HBc positive patients and 1.86 (95% CI 1.41-2.42) in anti-HBc negative ones. By Cox multiple regression, there was no association of serum anti-HBc with HCC development (HR 1.03, 95% CI 0.69-1.52) or liver-related deaths incidence (HR 1.21; 95% CI 0.76-1.95). CONCLUSIONS: In comparison with anti-HBc negative subjects, serum anti-HBc positive patients with HCV-related/HBsAg negative cirrhosis treated with IFN monotherapy did not show a greater risk of HCC.

Mangia A, Antonucci F, Brunetto M, Capobianchi M, Fagiuoli S, Guido M, Farci P, Lampertico P, Marzano A, Niro G, Pisani G, Prati D, Puoti M, Raimondo G, Santantonio T, Smedile A, Lauria F, Anonymous00030. · Liver Unit, IRCCS, Ospedale "Casa Sollievo della Sofferenza" San Giovanni Rotondo, Italy. · Dig Liver Dis. · Pubmed #18321798 No free full text.

Abstract: Molecular assays are instrumental in the clinical management of viral hepatitis. During the past years, a wide variety of molecular assays have been developed and implemented. This considerably improved the understanding of the natural history and pathogenesis of Hepatitis B virus (HBV), Hepatitis C virus (HCV) or Hepatitis delta virus (HDV) hepatitis, but also caused uncertainties in the selection of the most appropriate assays for clinical requirements. Indeed, a rational choice and application of these assays requires adequate knowledge of the performance of the single test. Moreover, the choice of the most accurate assay for patients' needs and physicians' objectives, needs to be oriented to specific contexts, such as diagnosis, management or treatment. In the past, a hurdle in the routine use of assays for hepatitis viruses nucleic acid quantification was represented by the availability of only "home brew" methods which lacked standardization. Major improvement in addressing the use of molecular assays for viral hepatitis has been derived from recent standardization procedures that allowed a comparison between different tests after results were given as International Units. In addition, it should be reminded that, before getting into the market, molecular assays should be approved by European regulation authorities and validated using internationally recognized standards. A subsequent clinical validation should address the diagnostic accuracy of the assay. These proceedings have the aim of identifying which molecular tests, among those currently available, meet clinical requirements for each specific application.

Mangia A, Minerva N, Bacca D, Cozzolongo R, Ricci GL, Carretta V, Vinelli F, Scotto G, Montalto G, Romano M, Cristofaro G, Mottola L, Spirito F, Andriulli A. · Gastroenterology, Istituto di Ricovero e Cura a Carattere Scientifico, Casa Sollievo della Sofferenza Hospital, San Giovanni Rotondo, Italy. · Hepatology. · Pubmed #18069698 No free full text.

Abstract: It was hypothesized that in hepatitis C virus (HCV) genotype 1 patients, variable treatment duration individualized by first undetectable HCV RNA is as effective as standard 48-week treatment. Patients (n = 696) received peginterferon alfa-2a, 180 mg/week, or peginterferon alfa-2b, 1.5 mg/kg/week, plus ribavirin, 1000-1200 mg/day, for 48 weeks (standard, n = 237) or for 24, 48, or 72 weeks if HCV-RNA-negative at weeks 4, 8, or 12, respectively (variable, n = 459). Sustained virologic response (SVR) was achieved in 45.1% [95% confidence interval (CI) 38.8-51.4] of the patients in the standard group and in 48.8% (CI 44.2-53.3) of the patients in the variable group (P = 0.37). The percentages of patients who first achieved undetectable HCV RNA at weeks 4, 8, or 12 were 26.7%, 27.8%, and 11.3%, respectively. In the standard treatment group, 87.1%, 70.3%, and 38.1% of patients who first achieved undetectable HCV RNA at 4, 8, or 12 weeks attained SVRs, respectively. In the variable group, corresponding SVR rates were 77.2%, 71.9%, and 63.5%. Low viremia levels and young age were independent predictors of response at week 4 [rapid virologic response (RVR)]. RVR patients with baseline viremia >or=400,000 IU/mL achieved higher SVR rates when treated for 48 weeks rather than 24 weeks (86.8% versus 73.1%, P = 0.14). The only predictive factor of SVR in RVR patients was advanced fibrosis. Conclusion: Variable treatment duration ensures SVR rates similar to those of standard treatment duration, sparing unnecessary side effects and costs.

Pazienza V, Clément S, Pugnale P, Conzelman S, Foti M, Mangia A, Negro F. · Division of Clinical Pathology, University Hospital, Geneva, Switzerland. · Hepatology. · Pubmed #17465001 No free full text.

Abstract: Both molecular and clinical evidence support a link between HCV infection and insulin resistance. We examined the in vitro interaction between the HCV core protein of genotypes 3a and 1b with the insulin-signaling pathway. We measured the expression levels of insulin receptor substrate 1 (IRS-1), IRS-2, and other factors involved in the insulin signal pathway in a human hepatoma cell line (Huh-7) transiently expressing the HCV core protein of genotypes 3a or 1b by molecular biology and biochemical techniques. The IRS-1 (but not IRS-2) protein level was significantly reduced in Huh-7 expressing the core protein of both genotypes 3a and 1b, as compared to cells transfected with the empty vector. However, while the core protein of genotype 3a promoted IRS-1 degradation through the downregulation of peroxisome proliferator-activated receptor gamma (PPARgamma) and by upregulating the suppressor of cytokine signal 7 (SOCS-7), the core protein of genotype 1b activated the mammalian target of rapamycin (mTOR). We confirmed these findings by using agonists for PPARgamma (rosiglitazone) or short interfering RNAs for SOCS-7. CONCLUSION: Despite the small sequence divergence of the HCV core proteins of genotypes 3a and 1b, the 2 proteins appear to interfere with the insulin signaling pathway using genotype-specific mechanisms.

Bruno S, Stroffolini T, Colombo M, Bollani S, Benvegnù L, Mazzella G, Ascione A, Santantonio T, Piccinino F, Andreone P, Mangia A, Gaeta GB, Persico M, Fagiuoli S, Almasio PL, Anonymous00048. · Liver Unit, Department of Medicine, AO Fatebenefratelli e Oftalmico, Milan, Italy. · Hepatology. · Pubmed #17326216 No free full text.

Abstract: The effect of achieving a sustained virological response (SVR) following interferon-alpha (IFNalpha) treatment on the clinical outcomes of patients with HCV-related cirrhosis is unknown. In an attempt to assess the risk of liver-related complications, HCC and liver-related mortality in patients with cirrhosis according to the response to IFNalpha treatment, a retrospective database was developed including all consecutive patients with HCV-related, histologically proven cirrhosis treated with IFNalpha monotherapy between January 1992 and December 1997. SVR was an undetectable serum HCV-RNA by PCR 24 weeks after IFNalpha discontinuation. HCC was assessed by ultrasound every 6 months. Independent predictors of all outcomes were assessed by Cox regression analysis. Of 920 patients, 124 (13.5%) were classified as achieving a SVR. During a mean follow-up of 96.1 months (range: 6-167) the incidence rates per 100 person-years of liver-related complications, HCC and liver-related death were 0, 0.66, and 0.19 among SVR and 1.88, 2.10, and 1.44 among non-SVR (P<0.001 by log-rank test). Multivariate analyses found that non-SVR was associated with a higher risk of liver-related complications (hazard ratio, HR, not applicable), HCC (HR 2.59; 95% CI 1.13-5.97) and liver-related mortality (HR 6.97; 95% CI 1.71-28.42) as compared to SVR. CONCLUSION: Thus, in patients with HCV-related, histologically proven cirrhosis, achievement of a SVR after IFNalpha therapy was associated with a reduction of liver-related mortality lowering both the risk of complications and HCC development. Irrespective of SVR achievement, all patients should continue surveillance because the risk of occurrence of HCC was not entirely avoided.

Andriulli A, Dalgard O, Bjøro K, Mangia A. · Division of Gastroenterology, "Casa Sollievo della Sofferenza" Hospital, IRCCS, 71013 San Giovanni Rotondo, Italy. · Dig Liver Dis. · Pubmed #16916631 No free full text.

Abstract: BACKGROUND: We have shown that 12-14 weeks treatment is effective in HCV-2 or -3 patients with undetectable HCV-RNA after 4 weeks of therapy (rapid virologic response). PATIENTS: To identify predictors of sustained virologic response, rapid virologic response and relapse following short treatment, we pooled data from the original Italian and Norwegian studies. Four hundreds and three patients were treated with PegIFN alpha-2b (1.0, n=281 or 1.5 microg/kg, n=122) and ribavirin (800-1200 mg) for 12-14 or 24 weeks, depending on negative or positive HCV-RNA at week 4. RESULTS: Sustained virologic response differed between cases with and without rapid virologic response (85% versus 62%, P<0.0001), mild and severe fibrosis (83% versus 67%, P=0.004), and HCV-2 and -3 (81% versus 73%, P=0.05). In a regression model, RVR (odds ratio 3.49, confidence interval 1.73-5.36) and mild fibrosis (odds ratio 2.91, confidence interval 1.57-5.38) independently predicted sustained virologic response. Rapid virologic response was obtained in 274 (68%) patients, 163/242 (67%) HCV-2, and 111/161 (69%) HCV-3. Patients with RVR had more frequently mild fibrosis (70% versus 54%, P=0.03), and high PegIFN dose (78% versus 64%, P=0.005). In a regression model, mild fibrosis independently predicted rapid virologic response (odds ratio 1.87, confidence interval 1.10-3.16). In rapid virologic response patients, sustained virologic response was achieved in 85% of both HCV-2 and -3. Virologic relapse was observed in 10.6% rapid virologic response patients and was more frequent among those with low ALT (14% versus 2%, P=0.04). CONCLUSION: In HCV-2 or -3, the HCV-RNA status after 4 weeks of therapy may guide treatment duration. HCV-2 and HCV-3 patients with severe fibrosis are less likely to experience both rapid virologic response and sustained virologic response, and more frequently relapse after a 12 or 14 weeks duration of antiviral therapy.

Leandro G, Mangia A, Hui J, Fabris P, Rubbia-Brandt L, Colloredo G, Adinolfi LE, Asselah T, Jonsson JR, Smedile A, Terrault N, Pazienza V, Giordani MT, Giostra E, Sonzogni A, Ruggiero G, Marcellin P, Powell EE, George J, Negro F, Anonymous00041. · IRCSS de Bellis, Castellana Grotte, Italy. · Gastroenterology. · Pubmed #16697727 No free full text.

Abstract: BACKGROUND & AIMS: Steatosis is a frequent histologic finding in chronic hepatitis C (CHC), but it is unclear whether steatosis is an independent predictor for liver fibrosis. We evaluated the association between steatosis and fibrosis and their common correlates in persons with CHC and in subgroup analyses according to hepatitis C virus (HCV) genotype and body mass index. METHODS: We conducted a meta-analysis on individual data from 3068 patients with histologically confirmed CHC recruited from 10 clinical centers in Italy, Switzerland, France, Australia, and the United States. RESULTS: Steatosis was present in 1561 patients (50.9%) and fibrosis in 2688 (87.6%). HCV genotype was 1 in 1694 cases (55.2%), 2 in 563 (18.4%), 3 in 669 (21.8%), and 4 in 142 (4.6%). By stepwise logistic regression, steatosis was associated independently with genotype 3, the presence of fibrosis, diabetes, hepatic inflammation, ongoing alcohol abuse, higher body mass index, and older age. Fibrosis was associated independently with inflammatory activity, steatosis, male sex, and older age, whereas HCV genotype 2 was associated with reduced fibrosis. In the subgroup analyses, the association between steatosis and fibrosis invariably was dependent on a simultaneous association between steatosis and hepatic inflammation. CONCLUSIONS: In this large and geographically different group of CHC patients, steatosis is confirmed as significantly and independently associated with fibrosis in CHC. Hepatic inflammation may mediate fibrogenesis in patients with liver steatosis. Control of metabolic factors (such as overweight, via lifestyle adjustments) appears important in the management of CHC.

Iacobellis A, Fusilli S, Mangia A, Clemente R, Festa V, Giacobbe A, Facciorusso D, Niro G, Conoscitore P, Andriulli A. · Division of Gastroenterology, Casa Sollievo della Sofferenza Hospital, IRCCS, San Giovanni Rotondo, Italy. · Aliment Pharmacol Ther. · Pubmed #16225484 links to  free full text

Abstract: BACKGROUND: Prior studies suggest that platelet counts of <140 000/microL can discriminate patients with different stages of fibrosis. AIM: To determine the added value of abdominal ultrasound analysis of morphological liver features in increasing the diagnostic accuracy of platelet counts for the prediction of liver fibrosis at histology. METHODS: In a retrospective study, clinical records of 1143 chronic hepatitis C patients at their first presentation, naives to both liver biopsy and anti-viral treatment, were reviewed. Sensitivity, specificity, positive and negative predictive values, positive and negative likelihood ratios of following indices were evaluated singularly or in combination: platelet counts <140 000/microL; nodular liver surface, spleen and portal vein size. RESULTS: All indices had specificity rate of > or =90% in excluding bridging fibrosis/cirrhosis, whereas sensitivity was acceptable (51%) for only platelet counts <140 000/microL. None of the ultrasonographic parameters singularly evaluated and reached an acceptable sensitivity rate. For ruling cirrhosis in or out, specificity rate was > or =82% for all tests, with the highest value reported by portal vein size. Low platelet counts plus nodular liver surface had the best sensitivity. CONCLUSIONS: No additional significant predictive value was given by adding ultrasonographic parameters to low platelet counts, whereas only a mild non-significant improvement in sensitivity was obtained combining platelet counts <140 000/microL with the presence of nodular liver surface. The platelet counts <140 000/microL showed the best predictive value for including both significant fibrosis and cirrhosis.