Publications by authors named "Giuseppina Brancaccio"

55 Publications

Ultra-deep sequencing reveals high prevalence and broad structural diversity of hepatitis B surface antigen mutations in a global population.

PLoS One 2017 4;12(5):e0172101. Epub 2017 May 4.

Bioscientia Institute for Medical Diagnostics, Ingelheim, Germany.

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.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0172101PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5417417PMC
September 2017

Real-life data on potential drug-drug interactions in patients with chronic hepatitis C viral infection undergoing antiviral therapy with interferon-free DAAs in the PITER Cohort Study.

PLoS One 2017 28;12(2):e0172159. Epub 2017 Feb 28.

Division of Infectious Diseases, Azienda Ospedaliera Ospedale Niguarda Ca' Granda, Milan, Italy.

Background: There are few real-life data on the potential drug-drug interactions (DDIs) between anti-HCV direct-acting antivirals (DAAs) and the comedications used.

Aim: To assess the potential DDIs of DAAs in HCV-infected outpatients, according to the severity of liver disease and comedication used in a prospective multicentric study.

Methods: Data from patients in 15 clinical centers who had started a DAA regimen and were receiving comedications during March 2015 to March 2016 were prospectively evaluated. The DDIs for each regimen and comedication were assigned according to HepC Drug Interactions (www.hep-druginteractions.org).

Results: Of the 449 patients evaluated, 86 had mild liver disease and 363 had moderate-to-severe disease. The use of a single comedication was more frequent among patients with mild liver disease (p = 0.03), whereas utilization of more than three drugs among those with moderate-to-severe disease (p = 0.05). Of the 142 comedications used in 86 patients with mild disease, 27 (20%) may require dose adjustment/closer monitoring, none was contraindicated. Of the 322 comedications used in 363 patients with moderate-to-severe liver disease, 82 (25%) were classified with potential DDIs that required only monitoring and dose adjustments; 10 (3%) were contraindicated in severe liver disease. In patients with mild liver disease 30% (26/86) used at least one drug with a potential DDI whereas of the 363 patients with moderate-to-severe liver disease, 161 (44%) were at risk for one or more DDI.

Conclusions: Based on these results, we can estimate that 30-44% of patients undergoing DAA and taking comedications are at risk of a clinically significant DDI. This data indicates the need for increased awareness of potential DDI during DAA therapy, especially in patients with moderate-to-severe liver disease. For several drugs, the recommendation related to the DDI changes from "dose adjustment/closer monitoring", in mild to moderate liver disease, to "the use is contraindicated" in severe liver disease.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0172159PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5330484PMC
September 2017

Multiclass HCV resistance to direct-acting antiviral failure in real-life patients advocates for tailored second-line therapies.

Liver Int 2017 04 20;37(4):514-528. Epub 2017 Jan 20.

Infectious Diseases Unit, Department of Social Health (DISSAL) of the University of Genoa, IRCCS S. Martino-IST, Genoa, Italy.

Background & Aims: Despite the excellent efficacy of direct-acting antivirals (DAA) reported in clinical trials, virological failures can occur, often associated with the development of resistance-associated substitutions (RASs). This study aimed to characterize the presence of clinically relevant RASs to all classes in real-life DAA failures.

Methods: Of the 200 virological failures that were analyzed in 197 DAA-treated patients, 89 with pegylated-interferon+ribavirin (PegIFN+RBV) and 111 without (HCV-1a/1b/1g/2/3/4=58/83/1/6/24/25; 56.8% treatment experienced; 65.5% cirrhotic) were observed. Sanger sequencing of NS3/NS5A/NS5B was performed by home-made protocols, at failure (N=200) and whenever possible at baseline (N=70).

Results: The majority of the virological failures were relapsers (57.0%), 22.5% breakthroughs, 20.5% non-responders. RAS prevalence varied according to IFN/RBV use, DAA class, failure type and HCV genotype/subtype. It was 73.0% in IFN group vs 49.5% in IFN free, with the highest prevalence of NS5A-RASs (96.1%), compared to NS3-RASs (75.9% with IFN, 70.5% without) and NS5B-RASs (66.6% with IFN, 20.4% without, in sofosbuvir failures). In the IFN-free group, RASs were higher in breakthrough/non-responders than in relapsers (90.5% vs 40.0%, P<.001). Interestingly, 57.1% of DAA IFN-free non-responders had a misclassified genotype, and 3/4 sofosbuvir breakthroughs showed the major-RAS-S282T, while RAS-L159F was frequently found in sofosbuvir relapsers (18.2%). Notably, 9.0% of patients showed also extra target RASs, and 47.4% of patients treated with ≥2 DAA classes showed multiclass resistance, including 11/11 NS3+NS5A failures. Furthermore, 20.0% of patients had baseline-RASs, which were always confirmed at failure.

Conclusions: In our failure setting, RAS prevalence was remarkably high in all genes, with a partial exception for NS5B, whose limited resistance is still higher than previously reported. This multiclass resistance advocates for HCV resistance testing at failure, in all three genes for the best second-line therapeutic tailoring.
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http://dx.doi.org/10.1111/liv.13327DOI Listing
April 2017

Reactivation of hepatitis B virus in cancer patients treated with chemotherapy for solid tumors. Is the prophylaxis really required?

Dig Liver Dis 2017 Feb 16;49(2):197-201. Epub 2016 Nov 16.

Division of Infectious Diseases and Viral Hepatitis, Naples, Italy.

Background: Reactivation of hepatitis B virus during cancer chemotherapy for non-hematological tumors is not fully clear.

Aim: To evaluate the risk of hepatitis B virus reactivation in carriers of hepatitis B virus cancer patients treated with chemotherapy for solid tumors.

Methods: Two hundred sixty-seven patients with solid tumors were consecutively enrolled: 13 (4.8%) were hepatitis B s-antigen positive, of whom 6 were documented inactive carriers and 7 had chronic liver disease. Thirty-two patients (12%) were hepatitis B s-antigen negative/hepatitis B c-antibody positive. Hepatitis B virus inactive carriers were followed every 3 months by alanine aminotransferases, hepatitis B virus-DNA; whereas hepatitis B virus occult carriers were followed every 3 months by alanine aminotransferases and hepatitis B s-antigen.

Results: None of the 38 total patients with inactive or occult B infection who did not receive prophylaxis presented hepatitis B virus reactivation during the follow-up period.

Conclusion: This study suggests that, in hepatitis B s-antigen negative patients who undergo chemotherapy for solid tumors, hepatitis B and c-antibody screening results are not relevant to clinical decision and can be avoided. Larger studies are needed to establish whether the risk of reactivation of HBV during chemotherapy is negligible in this subset of patients and they could not be monitored for HBV reactivation.
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http://dx.doi.org/10.1016/j.dld.2016.11.004DOI Listing
February 2017

Characteristics of liver cirrhosis in Italy: Evidence for a decreasing role of HCV aetiology.

Eur J Intern Med 2017 Mar 9;38:68-72. Epub 2016 Nov 9.

Gastroenterology & Hepatology Unit, Di. Bi.MI. S., University of Palermo, Italy. Electronic address:

Background: Previous cross-sectional studies have shown that hepatitis C virus (HCV) infection had been the main agent associated with liver cirrhosis in Italy.

Aim: To assess epidemiological, laboratory and clinical features of liver cirrhosis in Italy in 2014.

Patients: Out of the 2557 consecutive subjects evaluated in 16 hospitals located throughout Italy in 2014, 832 (32.6%) had liver cirrhosis and were enrolled in this study.

Results: The mean age of subjects was 60.3years, with a male/female ratio of 1.7; 74.9% of cases had Child A cirrhosis and 17.9% superimposed hepatocellular carcinoma. HCV infection, alone or in combination with other aetiologic agents, was responsible of 58.6% of cases, HBV aetiology accounted for the 17.6% and alcohol abuse for the 16.0%. Compared with virus-related cirrhotic patients, those alcohol-related more frequently showed decompensation (p=0.02).

Conclusions: Compared to previous surveys performed in 1992 and in 2001, we observe a statistically significant (p<0.05) decreasing role of both HCV infection and alcohol abuse as aetiologic agents of liver cirrhosis in Italy, explaining, at least in part, the slow, progressive decline of the mortality rate for liver cirrhosis in the last decades in this country (from 34.5 deaths/100,000 inhabitants in1980 to 10.8 in 2012).
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http://dx.doi.org/10.1016/j.ejim.2016.10.012DOI Listing
March 2017

Hepatitis delta infection in Italian patients: towards the end of the story?

Infection 2017 Jun 5;45(3):277-281. Epub 2016 Nov 5.

Gastroenterology and Hepatology Unit, Biomedical Department of Internal and Specialized Medicine (Di.Bi.M.I.S.), University of Palermo, Piazza delle Cliniche, 2, 90127, Palermo, Italy.

Background: The endemicity of hepatitis delta virus infection in Italy has decreased in the last decades.

Aim: To evaluate the current epidemiology of chronic delta infection in Italy and to compare the present findings with the corresponding figures from the previous studies.

Methods: A cross-sectional study involving 16 referral centres scattered all over the country in 2014.

Results: Out of the 513 hepatitis B surface antigen-positive subjects enrolled, 61 (11.9%) were anti-delta positive, with a sex ratio (M/F) of 2.05. The majority (80.3%) of them was 50 years or older, while the proportion of subjects younger than 30 years of age was as low as 3.3%. No difference was detected by geographical area of residence. The presence of liver cirrhosis was diagnosed in 52.4% of cases. In comparison to previous studies, a further shift towards the oldest age groups and an increasing proportion of subjects having liver cirrhosis among all anti-delta-positive subjects are observed.

Conclusions: Currently, hepatitis delta infection mostly affects old people who have an advanced but indolent liver disease, reflecting a survival effect. The defective hepatitis delta virus is near to disappear in the country, where it has been discovered in the second half of 70s.
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http://dx.doi.org/10.1007/s15010-016-0956-1DOI Listing
June 2017

Epidemiological and clinical scenario of chronic liver diseases in Italy: Data from a multicenter nationwide survey.

Dig Liver Dis 2016 Sep 26;48(9):1066-71. Epub 2016 May 26.

Gastroenterology & Hepatology Unit, Di.Bi.MI.S. University of Palermo, Palermo, Italy.

Background: The last Italian prevalence survey on chronic liver diseases (CLD) was performed in 2001. The present study evaluated the changes occurring over thirteen years.

Methods: We enrolled 2,557 CLD consecutive patients in 16 Italian liver units in 2014.

Results: HBV etiology accounted for 513 (20.2%) cases, alone in 439 and associated with HCV and/or alcohol abuse in 74. Of these 513, 11.9% were anti-HDV-positive and 7.2% HBeAg-positive. HCV alone was responsible for 50.3% of CLD and with alcohol abuse for 5.9%. HCV RNA was detected in 64.0% of the anti-HCV-positive patients tested. HCV genotyping, performed for 899 patients, showed genotype-1a, 1b, 2, 3, 4 and 5 respectively in 16.5%, 45.5%, 15.4%, 8.2%, 15.1% and 0.2%. Alcohol abuse alone was responsible for 6.4% of cases and NAFLD/NASH for 6.3%. Liver cirrhosis (p<0.001) and HCC (p<0.001) were more frequent in alcoholic than viral etiologies. HCV and alcohol etiologies were more frequent in 2001 than 2014 (from 69.9% to 59.9% and from 23.0% to 12.3%, respectively). HBV showed a similar impact. In all etiologies, the 2001 CLD cases were 10 years younger and with a significantly lower rate of cirrhosis than the 2014 cases.

Conclusion: The changes in HCV, HBV and alcohol etiologies may help apply more appropriate healthcare strategies.
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http://dx.doi.org/10.1016/j.dld.2016.05.014DOI Listing
September 2016

Patterns of treatment and costs of intermediate and advanced hepatocellular carcinoma management in four Italian centers.

Ther Clin Risk Manag 2015 19;11:1603-12. Epub 2015 Oct 19.

Scuola Superiore Sant'Anna, Pisa, Italy.

Background: Hepatocellular carcinoma (HCC) is a severe health condition associated with high hospitalizations and mortality rates, which also imposes a relevant economic burden.

Purpose: The aim of the present survey is to investigate treatment strategies and related costs for HCC in the intermediate and advanced stages of the disease.

Patients And Methods: The survey was conducted in four Italian centers through structured interviews with physicians. Information regarding the stage of disease, treatments performed, and related health care resource consumption was included in the questionnaire. Direct health care cost per patient associated with the most relevant treatments such as sorafenib, transarterial chemoembolization (TACE), and transarterial radioembolization (TARE) was evaluated.

Results: Between 2013 and 2014, 285 patients with HCC were treated in the four participating centers; of these, 80 were in intermediate stage HCC (Barcelona Clinic Liver Cancer Classification [BCLC] B), and 57 were in the advanced stage of the disease (BCLC C). In intermediate stage HCC, the most frequent first-line treatment was TACE (63%) followed by sorafenib (15%), radiofrequency ablation (14%), and TARE (1.3%). In the advanced stage of HCC, the most frequently used first-line therapy was sorafenib (56%), followed by best supportive care (21%), TACE (18%), and TARE (3.5%). The total costs of treatment per patient amounted to €12,214.54 with sorafenib, €13,418.49 with TACE, and €26,106.08 with TARE. Both in the intermediate and in the advanced stage of the disease, variability in treatment patterns among centers was observed.

Conclusion: The present analysis raises for the first time the awareness of the overall costs incurred by the Italian National Healthcare System for different treatments used in intermediate and advanced HCC. Further investigations would be important to better understand the effective health care resource usage.
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http://dx.doi.org/10.2147/TCRM.S88208DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4621183PMC
November 2015

Increased liver stiffness in idiopathic pulmonary fibrosis: a pilot study.

Sarcoidosis Vasc Diffuse Lung Dis 2015 Jul 22;32(2):176-80. Epub 2015 Jul 22.

FedericoII University of Naples, Italy.

Purpose: There is evidence that pulmonary, hepatic and renal fibrosis may share common pathogenetic pathways. Aim of our study was to measure liver stiffness in patients affected by clinically stable idiopathic pulmonary fibrosis (IPF).

Methods: Twenty-nine cases (24 M; mean age±SD: 67±8.3 yrs; 19 ex-smokers) along with fifteen age- and sex-matched healthy volunteers were enrolled. Liver conventional ultrasound examination and transient ultrasound elastography (TUE) were realized by two independent operators.

Results: Mild/moderate steatosis was identified in 1 control and 8 IPF cases (6.6% and 27.5%); severe steatosis in 2 IPF patients (7%). Mean TUE measurements were increased in 11 IPF cases (38%) as compared to controls (6.4±2.2 kPa vs 5.2±0.4 kPa; p=0.02).

Conclusions: To our knowledge, this is the first report suggesting that liver stiffness is increased in more than one-third of IPF patients. Application of novel methodologies should be encouraged for investigating further IPF.
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July 2015

Individualized treatment of genotype 1 naïve patients: an Italian multicenter field practice experience.

PLoS One 2014 23;9(10):e110284. Epub 2014 Oct 23.

Università degli Studi del Piemonte Orientale, Department of Internal Medicine, Novara, Italy.

Background: Triple therapy including Telaprevir or Boceprevir still represents in many European countries the standard of care for patients with Hepatitis C Virus genotype 1 infection. The number of patients who received this treatment resulted generally lower than expected. We investigated, among naïve patients, number and characteristics of treatment candidates who were started on triple or dual therapy in comparison to those who were deferred.

Patients And Methods: 621 naïve treatment candidates were prospectively evaluated at each center. Factors associated with decision to defer or treat with dual or triple therapy were investigated by univariate and multivariate analyses. Rates of Sustained Virological Response and safety profile were analysed.

Results: Of candidates to treatment, 33% did not received it. It was mostly due to high risk of Interferon-induced decompensation. Of 397 patients who were started on treatment, 266 (67%) received triple, 131 dual. Among patient receiving treatment, unfavorable IL28B, severe liver damage and higher albumin were independently associated with the physician decision to administer triple therapy. Sustained Virological Response after dual therapy was 66.4%, after triple 73.7% (p = 0.14). 142 patients received Telaprevir. The choice of Telaprevir-based therapy was associated with higher Body Mass Index and advanced liver disease. Sustained Virological Response rates were 71.1% after Telaprevir and 76.6% after Boceprevir.

Conclusions: Individualizing treatment with available regimens allows to maximize Sustained Virological Response and to reduce the number of patients who remain untreated. High proportion of patients with severe liver damage urgently need Interferon free treatment.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0110284PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4207756PMC
June 2015

Interleukin-28B genetic variants in untreated Italian HCV-infected patients: a multicentre study.

Liver Int 2015 Feb 17;35(2):482-8. Epub 2014 Jul 17.

Liver Unit, Hospital 'Casa Sollievo della Sofferenza', San Giovanni Rotondo, Italy.

Background & Aims: Different prevalence of favourable IL28BCC genotype have been reported in studies performed in different countries around the world. Data on distribution of IL28B genotypes in healthy Italian subjects are lacking.

Methods: Studies on prospectively collected untreated chronic HCV-infected Italian patients led to conflicting results. To investigate the prevalence of IL28B genotypes in untreated HCV-infected patients and in subjects able to clear HCV, and to compare them to the prevalence registered in healthy Italian controls. To evaluate IL28B prevalence across different HCV genotypes.

Results: IL28BCC was observed in 30.9% of chronic HCV patients, in 71.0% of subjects able to clear HCV infection and in 41.6% of the Italian controls. The frequency of IL28BCC was higher in HCV genotype 2 and 3 than in 1 (38.3 vs. 28.2) (P = 0.02). Levels of ALT higher in IL28BCC than in non-CC were observed regardless of HCV genotypes (P = 0.0014).

Conclusions: IL28BCC frequencies progressively decline from subjects with spontaneous HCV clearance to normal non-infected subjects and to chronically infected. This study suggests that patients with IL28BCC, if genotype 1, are able to clear HCV more often than if genotype 2 and 3 infected, and that CC genotype is associated with higher grade of necro-inflammation.
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http://dx.doi.org/10.1111/liv.12630DOI Listing
February 2015

An a priori prediction model of response to peginterferon plus ribavirin dual therapy in naïve patients with genotype 1 chronic hepatitis C.

Dig Liver Dis 2014 Sep 20;46(9):818-25. Epub 2014 Jun 20.

Hepatology and Liver Transplantation Unit, University of Tor Vergata, Roma, Italy.

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 <30% sustained virological response probability for not recommending Peg-interferon+ribavirin, 100 patients (25.6%) in the validation cohort were predicted a priori to fail this regimen. Assuming a ≥80% sustained virological response probability as a threshold to continue with Peg-interferon+ribavirin, 61 patients were predicted to obtain sustained virological response, and 55 of them (90.2%) eventually did.

Conclusions: This model uses easily determined variables for a personalized estimate of the probability of sustained virological response with Peg-interferon+ribavirin, allowing to identify patients who may benefit from conventional therapy.
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http://dx.doi.org/10.1016/j.dld.2014.05.015DOI Listing
September 2014

Active recruitment strategy in disadvantaged immigrant populations improves the identification of human immunodeficiency but not of hepatitis B or C virus infections.

Dig Liver Dis 2014 Jan 20;46(1):62-6. Epub 2013 Oct 20.

Viral Hepatitis Unit, Department of Internal Medicine, Second University, Naples, Italy. Electronic address:

Background: Barriers to access medical screening and care may underestimate the number of diseased subjects among immigrant populations.

Aims: To evaluate the prevalence of human immunodeficiency virus, hepatitis B virus and hepatitis C virus infections among immigrants recruited in a disadvantaged area.

Methods: The study enrolled all subjects seen between 1999 and 2009 at an on-site health and family counselling centre for immigrants. During the first 6 years of the study a pro-active recruitment was performed using a mobile unit.

Results: Overall 2681 subjects were enrolled (median age: 31 years; 52.8% males; 82.3% from Sub-Saharan Africa; 13.9% of the women were sex workers). A total of 206 subjects (7.6%) were hepatitis B surface antigen-positive, 84 (3.6%) were anti-hepatitis C virus-positive, 129 (5%) were anti-human immunodeficiency virus-positive, 84 (3.1%) were drug users, and 436 (16.3%) were alcohol abusers. The prevalence of hepatitis B surface antigen and anti-hepatitis C virus remained consistent throughout the study period, while the prevalence of human immunodeficiency virus significantly decreased. At multivariate analysis, hepatitis B virus infection was associated with male gender, hepatitis C virus infection with drug addiction, and human immunodeficiency virus infection was associated with female gender, drug addiction, and active recruitment.

Conclusions: An active recruitment strategy should be considered to reach disadvantaged populations at high risk of human immunodeficiency virus infection.
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http://dx.doi.org/10.1016/j.dld.2013.08.126DOI Listing
January 2014

Identification of naïve HCV-1 patients with chronic hepatitis who may benefit from dual therapy with peg-interferon and ribavirin.

J Hepatol 2014 Jan 20;60(1):16-21. Epub 2013 Aug 20.

Clinic of Infectious Diseases, University of Foggia, Italy.

Background & Aims: The pool of HCV genotype 1 patients likely to be cured by peg-interferon and ribavirin remains to be quantified.

Methods: In 1045 patients treated with peg-interferon and ribavirin, two therapeutic strategies were confronted: the first one evaluated only baseline variables associated with sustained virological response (SVR), and the second one included the rapid virologic response (RVR) in addition to baseline predictors. An 80% SVR rate was the threshold to retain a strategy as clinically relevant.

Results: Overall, 414 patients (39.6%) attained SVR. In the first strategy, the hierarchy of features independently associated with SVR was IL28B CC genotype (OR 5.082; CI 3.637-7.101), low (<400,000 IU) viremia (OR 2.907; CI 2.111-4.004), F0-F2 fibrosis (OR 1.631; CI 1.122-2.372) and type 2 diabetes (OR 0.528; CI 0.286-0.972). In the alternative strategy, SVR was associated with RVR (OR 6.273; CI 4.274-9.208), IL28B CC genotype (OR 3.306; CI 2.301-4.751), low viremia (OR 2.175; CI 1.542-3.070), and F0-F2 fibrosis (OR 1.506; CI 1.012-2.242). Combining the favorable baseline variables, the rates of SVR ranged from 42.4% to 83.3%, but only 66 patients (6.3%, overall) with all predictors could be anticipated to reach the >80% SVR threshold. Only 26.6% of no-RVR patients attained SVR. Among the 255 RVR patients, the likelihood of SVR was 61.8% in those with unfavorable predictors, 80% in the presence of a single predictor, and 100% when both predictors were present. By using this model, 200 patients (19.1%) were predicted to have an 80% chance of being cured with dual therapy.

Conclusions: A consistent subset of naïve HCV-1 patients, identified by some baseline characteristics and RVR, may benefit from dual treatment with peg-interferon and ribavirin.
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http://dx.doi.org/10.1016/j.jhep.2013.07.040DOI Listing
January 2014

Different changes in mitochondrial apoptotic pathway in lymphocytes and granulocytes in cirrhotic patients with sepsis.

Liver Int 2013 Jul 17;33(6):834-42. Epub 2013 Apr 17.

Department of Internal and Specialistic Medicine, Infectious Diseases and Viral Hepatitis Unit, Second University of Naples, Naples, Italy.

Background & Aims: Apoptosis regulates leucocyte response during bacterial infections. This study explored leucocyte apoptotic pathway in cirrhotic patients with or without infections or sepsis.

Methods: In cirrhotic patients with bacterial infection or sepsis, the expression of Caspase 9, Bcl-2 family proteins, which comprises pro-apoptotic molecules, such as Bax, and anti-apoptotic molecules, such as Bcl-2 and Bcl-xL, were measured in peripheral lymphocytes and granulocytes. Regulatory microRNAs MIR-15 and MIR-16 were also measured.

Results: This study enrolled 80 patients with cirrhosis, of whom 28 had no evidence of infections, 32 had bacterial infections and 20 had sepsis; reference values were obtained from 10 age-matched healthy subjects. An over-expression of Caspase-9 and pro-apoptotic protein Bax was found in lymphocytes of cirrhotic patients with infection or sepsis as compared with non-infected cases (P = 0.05 and 0.0001, respectively), while anti-apoptotic proteins Bcl-2 and Bcl-xL were downregulated. In granulocytes, lowest expression of pro-apoptotic protein Bax occurred in septic patients, while in cirrhotics with infections anti-apoptotic Bcl-2 and Bcl-xL were upregulated. Eight patients died; the survivors had less derangements in Bax, Bcl-2 and BcL-xL expression than non-survivors. The pro-apoptotic miRNA, MIR-15 and MIR-16, were upregulated in cirrhotics with bacterial infections.

Conclusions: Overall, the data show in lymphocytes, and not in granulocytes, an activation of the pro-apoptotic pathway in cirrhotic patients with bacterial infections, which correlates with the severity of the infection and the outcome.
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http://dx.doi.org/10.1111/liv.12169DOI Listing
July 2013

Restored function of HBV-specific T cells after long-term effective therapy with nucleos(t)ide analogues.

Gastroenterology 2012 Oct 14;143(4):963-73.e9. Epub 2012 Jul 14.

Laboratory of Viral Immunopathology, Unit of Infectious Diseases and Hepatology, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy.

Background & Aims: In patients with chronic hepatitis B virus (HBV) infection, persistent exposure to high concentrations of antigen can disrupt T-cell functions. It is not clear to what extent long-term suppression of HBV by nucleos(t)ide analogues can restore antiviral T-cell functions. We compared HBV-specific T-cell responses of patients treated with nucleos(t)ide analogues with those detected in other conditions of HBV control.

Methods: We analyzed intracellular levels of interferon gamma, interleukin-2, and tumor necrosis factor α in HBV-specific T cells after 10 days of stimulation with peptides covering the overall HBV genotype D sequence and ex vivo with selected CD8 epitopes and the corresponding HLA-A2 dextramers. Findings from patients treated with nucleos(t)ide analogues who had complete (HBV DNA negative/antibody to hepatitis B surface antigen positive) or partial (HBV DNA negative/hepatitis B surface antigen positive) control of their infections were compared with those of patients with spontaneous or interferon alfa-induced resolution of acute or chronic infections, inactive HBV carriers, or untreated hepatitis B e antigen-negative patients with chronic infections.

Results: Although HBV-specific T cells from nucleos(t)ide analogue-treated patients with complete control of infection were dysfunctional ex vivo, they had efficient responses after in vitro expansion. These responses were comparable to those of patients who spontaneously resolved acute HBV infection. Nucleos(t)ide analogue-treated patients who were HBV DNA negative but hepatitis B surface antigen positive had lower levels of T-cell responses but responses greater than those of untreated patients with chronic infection.

Conclusions: In vitro reactivity can be restored to T cells from patients with suppressed HBV infection following long-term treatment with nucleos(t)ide analogues, despite prolonged exposure to large loads of antigen. Immune therapies that increase the antiviral T-cell response might increase the likelihood of complete HBV control in patients undergoing long-term nucleos(t)ide analogue treatment.
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http://dx.doi.org/10.1053/j.gastro.2012.07.014DOI Listing
October 2012

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

J Hepatol 2012 Jun 16;56(6):1254-8. Epub 2012 Feb 16.

Clinic of Infectious Diseases, University of Bari, Policlinico, Bari, Italy.

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 5 years were included. Biochemical and virological tests were assessed every 3 months in all patients and HBsAg quantification was performed in 45/191. Reverse-transcriptase (RT) region was directly sequenced in virological breakthrough patients.

Results: One hundred and ninety-one patients (148 males, median age 53 years, 72 with compensated cirrhosis) responding to 60-month LAM monotherapy continued to receive LAM monotherapy beyond the initial 5 years and were followed for an additional 36-month median period (range 1-108). Virological response was maintained in 128/191 patients (67%) and HBsAg clearance was observed in 15/128 (11.7%) after a 32-month median period (range 1-65). The 63 remaining patients (33%) showed virological breakthrough after a 15-month median treatment (range 1-78). RT region analysis was performed in 38/63 breakthrough patients and LAM resistant mutations were found in 37/38. No significant side effects were observed.

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.
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http://dx.doi.org/10.1016/j.jhep.2012.01.022DOI Listing
June 2012

Changing aetiological factors of hepatocellular carcinoma and their potential impact on the effectiveness of surveillance.

Dig Liver Dis 2011 Nov;43(11):875-80

Dipartimento Malattie Infettive e Tropicali, Policlinico Umberto I, Rome, Italy.

Background: The aetiological factors of hepatocellular carcinoma may vary over time.

Aims: The study assessed the potential impact of the aetiological factors on the effectiveness of surveillance in real-world patients.

Methods: Multicentre, cross-sectional study enrolling consecutive hepatocellular carcinoma cases during a six month period.

Results: 1733 cases (1311 prevalent and 422 incident) were recruited (mean age 68.6 years; 46.1% cases over 70 years; 73.9% males; 95.3% with cirrhosis); 63.0% were hepatitis C virus positive and 23.7% were virus negative. Amongst incident HCCs, 34.5% were single ≤3cm and 54.4% met the Milan criteria; 61.6% were diagnosed during surveillance; virus negative patients showed the lowest rate of surveillance (51.0%). Surveillance was an independent predictor of detecting single HCCs ≤2cm (O.R.=5.4; 95% C.I.=2.4-12.4) or HCCs meeting the Milan criteria (O.R.=3.1; 95% C.I.=1.9-5.2). Compared with an earlier Italian survey, there was a higher proportion of elderly subjects (P<0.01), Child-Pugh class A cases (P<0.01), of virus-negative patients (P<0.01) and with single tumours ≤3cm (P<0.01) and a lower prevalence of hepatitis C virus positive individuals (P<0.01).

Conclusion: HCC is characterised by a growing prevalence of elderly patients and cases unrelated to hepatitis virus infections. The application of surveillance must be implemented, particularly amongst non-viral patients.
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http://dx.doi.org/10.1016/j.dld.2011.05.002DOI Listing
November 2011

Is spleen circulation impaired in systemic sclerosis and what is the role of liver fibrosis?

World J Gastroenterol 2011 Mar;17(12):1606-13

Department of Clinical and Experimental Medicine, Federico II University Medical School of Naples, 80131 Naples, Italy.

Aim: To investigate the spleen vascular involvement and the presence of liver fibrosis in a population of subjects with established systemic sclerosis (SSc).

Methods: In a cross-sectional fashion, 17 patients with SSc were compared with 18 patients suffering from hepatitis C virus (HCV)-related liver cirrhosis, grade A and B Child-Pugh classification. Eighteen non elderly subjects, apparently healthy, were used as the control group. Splenic artery resistivity index (SARI) at Doppler ultrasound, transient elastography of liver and nailfold capillaroscopy were the main outcomes.

Results: Transient elastography values of SSc patients were similar to those of controls; 5.2 ± 1.1 vs 4.5 ± 1, (P = 0.07). Median Alanine amino transferase (ALT) concentrations of cirrhotic patients were greater than those of controls and SSc patients, i.e. 66.5 (36-89) U/L vs 29 (22-34) U/L and 31 (22-41) U/L, respectively, (P = 0.005). SARI determinations in cirrhotic patients, although significantly higher than those found in controls and SSc patients, showed some degree of overlap with SSc patients, i.e. 0.59 vs 0.52 and 0.57, respectively, (P = 0.04). Mean systolic blood pressure was significantly higher in SSc patients than in cirrhotics and controls, i.e. 142 mmHg vs 128.2 mmHg and 127 mmHg, respectively, (P = 0.005). Mean diastolic blood pressure behaved in a similar fashion, i.e. 84 mmHg vs 72.2 mmHg and 76.9 mmHg (P = 0.005). Nailfold Capillaroscopy grades and diastolic blood pressure values correlated well with SARI results.

Conclusion: An enhanced resistivity of the splenic artery was found in patients suffering from SSc; they did not have evidence of splenomegaly as well as no liver fibrosis or any other form of liver damage.
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http://dx.doi.org/10.3748/wjg.v17.i12.1606DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3070133PMC
March 2011

Salvage therapy with tenofovir followed by adefovir maintenance in a cirrhotic patient with a lamivudine resistant HBV flare.

Infez Med 2009 Jun;17(2):105-8

Viral Hepatitis Unit and Research Doctorate in Experimental Medicine and Pharmacology, Second University, Naples, Italy.

A 36 year old man with chronic hepatitis B and cirrhosis was admitted in our Department for the onset of jaundice, ascites and ALT flare (x 35 u.n.v.) while under lamivudine treatment. Serum HBV-DNA was 1.48 x 10(6) IU/ml and lamivudine (LAM) resistance mutations were present. Tenofovir (TDF) 300 mg/day was added to LAM after its off-label use was authorised. HBV-DNA decreased in a biphasic manner and became undetectable by day 45. A parallel improvement in ALT and bilirubin values was detected. Tenofovir was substituted with adefovir dipivoxil 10 mg/day. Ten months after this switch HBV-DNA remained undetectable. Tenofovir is an effective salvage therapy for critically ill patients with LAM-resistant HBV flares and can be switched to adefovir after HBV-DNA becomes undetectable. Local cost and reimbursement policies are important determinants in antiviral therapy.
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June 2009

Influenza vaccination in patients with cirrhosis and in liver transplant recipients.

Vaccine 2009 May 5;27(25-26):3373-5. Epub 2009 Feb 5.

Department of Infectious Diseases, Viral Hepatitis Unit, Second University of Naples, Italy.

To assess the safety and immunogenicity of influenza vaccination, patients with cirrhosis undergoing treatment or not and liver transplant recipients under standard immunosuppression were vaccinated and followed up for 6 months. One month after vaccination, seroprotection rates and antibody GMTs against the three vaccine antigens were higher than baseline levels in all three patients groups. No differences in seroconversion and seroprotection rates were found within groups, but antibody GMTs against A/H1N1 and A/H3N2 strains were lower in liver transplant recipients than in patients with cirrhosis without treatment. No serious adverse events and no alteration of the liver function tests were observed. Patients with cirrhosis, including those under treatment, and liver transplant recipients benefit from influenza vaccination and can be safely immunized.
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http://dx.doi.org/10.1016/j.vaccine.2009.01.077DOI Listing
May 2009

Viral blips during long-term treatment with standard or double dose lamivudine in HBe antigen negative chronic hepatitis B.

World J Gastroenterol 2007 Nov;13(42):5642-7

Department of Infectious Diseases, Second University of Naples, Via Cotugno 1, c/o Osp. Gesu e Maria, Naples 80135, Italy.

Aim: To evaluate safety and effect on hepatitis B virus (HBV) suppression of a long-term treatment with lamivudine (LAM) at standard (100 mg/d) or double (200 mg/d) dose in chronic hepatitis B.

Methods: This was a case study with matched controls (1:3) in patients with chronic hepatitis B with anti-HBe antibodies.

Results: Twelve patients received LAM 200 mg/d and 35 LAM 100 mg/d, for a median of 28 mo. A primary response (PR; i.e. negative HBV-DNA with Amplicor assay) was achieved in 100% of LAM-200 patients and 83% of LAM-100 patients. A virological breakthrough occurred in 16.7 and 24.7%, respectively, of the PR-patients, with the appearance of typical LAM resistance mutations in all but one patient. Viremia blips (i.e. transient HBV-DNA below 80 IU/mL in patients who tested negative at Amplicor assay) were detected using a real time polymerase chain reaction (PCR) and occurred in seven out of nine patients with subsequent BT and in four out of 32 patients with end-of-study response (77.7% vs 12.5%; P = 0.001) at chi-square test). At the end of the study, 51.4% of LAM-100 patients and 83.3% of LAM-200 patients had remained stably HBV-DNA negative. Double-dose LAM was well tolerated.

Conclusion: Long-term treatment of anti-HBe positive chronic hepatitis B with double dose lamivudine causes a more profound and stable viral suppression as compared to conventional treatment.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4172745PMC
http://dx.doi.org/10.3748/wjg.v13.i42.5642DOI Listing
November 2007

Pegylated interferon alpha-2b as monotherapy or in combination with ribavirin in chronic hepatitis delta.

Hepatology 2006 Sep;44(3):713-20

Gastroenterology CSS Hospital, S.Giovanni Rotondo, and Gastroenterology Molinette Hospital and Unversity, Turin, Italy.

Therapy of chronic hepatitis delta with standard interferon therapy has met with limited efficacy. This study was designed to examine the efficacy and safety of peginterferon with or without ribavirin. Thirty-eight serum hepatitis B surface antigen- and HDV RNA-positive patients with alanine aminotransferase (ALT) more than 1.5 times the upper normal limit received peginterferon alpha-2b (1.5 microg/kg) alone as monotherapy (n=16) or in combination with ribavirin (n=22), for 48 weeks. Thereafter, all the patients were maintained on peginterferon for 24 weeks and followed for 24 weeks off therapy. The primary end point studied was the virological and biochemical response at the end of follow-up. HDV RNA was determined by single or nested polymerase chain reaction assays. Twenty-seven patients (71%), 11 receiving monotherapy and 16 receiving the combination treatment, completed the follow-up. At the end of treatment, a virological response was observed in 3 of the patients treated with peginterferon (19%) and in 2 of the patients treated with combination therapy (9%), and a biochemical response was observed in 6 (37.5%) and 9 patients (41%), respectively. In nonresponders, ALT diminished from a mean of 174+/-53 to 86+/-41 IU/L. At the end of follow-up, serum HDV RNA was negative in 8 patients (21%), and a biochemical response was detected in 10 patients (26%). Treatment was discontinued in 25% of the patients, and dosing was modified in 58%. In conclusion, a prolonged course of peginterferon alpha-2b resulted in clearance of serum HDV RNA and ALT normalization in a fifth of patients with chronic hepatitis D, while ribavirin had no effect on the viral clearance rate. Overall tolerance of therapy was poor.
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http://dx.doi.org/10.1002/hep.21296DOI Listing
September 2006

[Cutaneous myiasis from Cordylobia anthropophaga in a traveller returning from Senegal: a case study].

Infez Med 2005 Jun;13(2):109-11

Dipartimento di Malattie Infettive e Dipartimento di Anatomia Patologica, Seconda Universita di Napoli.

Myiasis is the infestation of human or animal tissues by fly larvae. The disease is widespread especially in tropical countries. Here we report a case of myiasis due to Cordylobia anthropophaga that occurred in a traveller returning from Senegal. This case has some peculiar characteristics, regarding the site of the lesion and the clinical presentation.
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June 2005

[Prevalence and risk factors for bacteriuria in patients with cirrhosis].

Infez Med 2005 Jun;13(2):103-8

Divisione Epatiti Virali Acute e Croniche, Dipartimento di Malattie Infettive, Seconda Universita di Napoli, Italy.

Bacterial infections occur frequently in patients with cirrhosis and may worsen the disease outcome. We investigated the prevalence of bacteriuria in 500 consecutive patients with cirrhosis, in different Child-Pugh stages (41.4% A; 40.8% B; 17% C) and analysed the associated risk factors. Most of the cirrhosis cases were virus related; alcohol abuse was recorded in 6.2% of the patients. Bacteriuria was detected in 139 (27.8%) cases: 32.4% were more than 100,000 cfu/ml; 7.9% between 100,000 and 1.000,000 cfu/ml and the remaining cases more than 1000,000 cfu/ml. Escherichia coli was the most frequent isolated agent (84.5%); Proteus spp. strains were detected only in bacteriuria with more than 100,000 cfu/ml. At univariate analysis, female gender, age and presence of diabetes were significantly associated to bacteriuria, while Child-Pugh stage and the presence of hepatocellular carcinoma were not. In a multivariate model, only female gender and diabetes were significantly associated to bacteriuria. These results indicate that advanced cirrhosis was not a risk for bacteriuria, that was associated rather to gender and diabetes, which are common risk factors for bacteriuria in non-cirrhotic patients.
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June 2005
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