Alessia Ciancio

Prevention of hepatitis B virus recurrence after liver transplantation in cirrhotic patients treated with lamivudine and passive immunoprophylaxis

BACKGROUND/AIMS Treatment with hepatitis B virus immune globulins (HBIG) or lamivudine has reduced the rate of hepatitis B recurrence after liver transplantation to approximately 50%. METHODS To further decrease hepatitis B recurrence, 33 hepatitis B virus (HBV)-related cirrhotic patients were treated with lamivudine before liver transplantation and with lamivudine together with low-dose HBIG (46 500 IU the first month followed by 5,000 lU/monthly) after surgery. RESULTS While on lamivudine, serum HBV DNA level decreased significantly in all patients and in 11 (33%) the Child-Pugh score improved. Twenty-six patients were transplanted. Among the 25 who survived for longer than 12 months, only one (4%) experienced a hepatitis B recurrence over an average follow-up of 31 months, a rate significantly lower (P = 0.0002) than the 50% recurrence rate among a historical control group of 12 patients. However, low-level HBV replication was detected sporadically throughout the follow-up in 64% of patients. CONCLUSIONS Over the medium-term, combined prophylaxis with lamivudine and HBIG significantly decreases the risk of hepatitis B recurrence after liver transplantation. Though low-level HBV infection recurred in two thirds of patients, the pathogenic expression of HBV was prevented.

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

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 μg/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. (HEPATOLOGY 2006;44:713–720.)

Position paper of the Italian Association for the Study of the Liver (AISF): The multidisciplinary clinical approach to hepatocellular carcinoma

Patients with hepatocellular carcinoma should be managed with a multidisciplinary approach framed in a network where all the diagnostic techniques and therapeutic resources are available in order to provide the optimal level of care. Given this assumption, the Coordinating Committee of the Italian Association for the Study of the Liver nominated a panel of experts to elaborate practical recommendations for the multidisciplinary management of hepatocellular carcinoma aiming to provide: (1) homogeneous and efficacious diagnostic and staging work-up, and (2) the best treatment choice tailored to patient status and tumour stage at diagnosis. The 2010 updated American Association for the Study of Liver Disease Guidelines for hepatocellular carcinoma were selected as the reference document. For each management issue, the American Association for the Study of Liver Disease recommendations were briefly summarised and discussed, according to both the scientific evidence published after their release and the clinical expertise of the Italian centres taking care of these patients. The Italian Association for the Study of the Liver expert panel recommendations are finally reported.

Lamivudine therapy in chronic delta hepatitis: A multicentre randomized-controlled pilot study

Background:  Delta virus (HDV)‐related chronic hepatitis is difficult to treat.

Effect of Preoperative Radiological Treatment of Hepatocellular Carcinoma Before Liver Transplantation: A Retrospective Study

AbstractPurpose: To assess the results of radiological treatment of patients with hepatocellular carcinoma (HCC) performed before orthotopic liver transplantation (OLT). Methods: Sixty-two transplanted patients with a total of 89 HCC nodules were studied; 50 lesions in 38 patients had been treated prior to OLT with transcatheter arterial chemoembolization (TACE: n=29), percutaneous ethanol injection (PEI; n=10), or combined therapy (TACE+PEI; n=11). The induced necrosis was pathologically evaluated. The recurrence rate after OLT in the treated group of patients (n=38) was compared with that in the non-treated group (n=24). Results: After TACE, necrosis was complete in 7 of 29 lesions (24.1%), partial in 11 of 29 (37.9%), and absent in 11 of 29 (37.9%). After PEI, necrosis was complete in 8 of 10 lesions (80%), and partial in 2 of 10 (20%). Using combined therapy, necrosis was complete in 11 of 11 lesions (100%). Four of 24 untreated and 4 of 38 treated patients did not survive OLT from causes not related to the HCC; 3 of 20 non-treated patients (15%) and 4 of 34 treated patients (11.8%) had post-OLT recurrence (these last four patients had undergone only TACE and did not have tumor necrosis at pathological examination). Conclusion: TACE of HCC prior to OLT had no influence on the recurrence rate. PEI and combined therapy (TACE + PEI) may be recommended in patients awaiting OLT.

Incidence of Type 2 Diabetes Mellitus and Glucose Abnormalities in Patients With Chronic Hepatitis C Infection by Response to Treatment: Results of a Cohort Study

BACKGROUND:Patients with chronic hepatitis C are at risk of developing type 2 diabetes mellitus (DM) and impaired fasting glucose (IFG), and this risk may increase among hepatitis C virus (HCV) patients not responding to an antiviral therapy.AIM:To compare the incidence of glucose abnormalities (IFG or DM) after an antiviral therapy between HCV+ patients with a long-term virological response (LTR) and nonresponders (NR; persistently positive HCV-RNA).METHODS:All 202 HCV+ patients without the baseline glucose abnormalities enrolled by our center in investigational trials or routinely treated with interferon (IFN)/peginterferon (Peg-IFN) (+/– ribavirin) from 1988 to 2001, with the available baseline sera stored at −80°C, were considered. The baseline data included age, sex, body mass index (BMI), viral load, genotype, liver histologic staging and steatosis, glucose, and cholesterol. The homeostatic assessment of insulin resistance (HOMA-IR) was calculated in the baseline serum. The incidence of IFG or DM at the end of follow-up was compared between patients with LTR and NR.RESULTS:After a median follow-up of 8.0 yr (range 5–16), the cumulative risk of DM (N = 7) or IFG (N = 33) among the 202 HCV+ included patients was 16.9% (95% confidence interval [CI] 11.3–22.5). The 8-yr risk was not significantly lower between LTRs (14.5%) compared to NRs (18.8%) (hazard ratio [HR] 0.60, CI 0.30–1.20, P= 0.16). The HR adjusted for the baseline risk factors for DM and the predictors of a poor response (age, sex, HOMA-IR, BMI, family history of diabetes, HCV genotype 1, high viral load, cirrhosis, and steatosis) was 0.88 (CI 0.38–2.02, P= 0.76). Among other factors, those more associated to IFG-DM were an increasing age (P= 0.017), a higher BMI (P= 0.054), and a family history of DM (P= 0.065).CONCLUSIONS:After adjustment for several baseline risk factors, the incidence of glucose abnormalities was not significantly different between LTRs and NRs. Our data suggest that HCV clearance does not significantly reduce the risk of glucose intolerance.

Digestive Endoscopy Is Not a Major Risk Factor for Transmitting Hepatitis C Virus

Context Controversy persists regarding the risk for transmission of hepatitis C virus (HCV) as a result of digestive-tract endoscopy. Contribution This prospective study of HCV-negative patients who underwent gastroscopy with the same endoscopes as HCV-positive patients showed no transmission of infection on follow-up 6 months later. Biopsy with reusable or disposable forceps did not increase the risk for HCV infection. Blood donors who were HCV negative without endoscopic exposure showed a few conversions to infected status an average of 2.5 years later. Implications The risk for HCV transmission by endoscopy is extremely low when standard instrument-cleaning techniques are used. The Editors Health carerelated procedures have been implicated in the transmission of a consistent proportion of contemporary hepatitis C virus (HCV) infections. The role of major surgical operations, such as cardiovascular, gynecologic, and orthopedic procedures, is well established. However, the role of less invasive procedures, such as digestive endoscopy, remains a matter of debate. A claim from a retrospective French study (1) that digestive endoscopic procedures are a major cause of HCV transmission among blood donors has not been substantiated by other authors (2, 3); acquisition of HCV through endoscopy has in fact been rarely reported in recent years (4, 5). Nevertheless, endoscopy as a vehicle for HCV transmission has been suspected since 1996, when blood banks in France and Italy suspended donors who reported a history of recent digestive endoscopy from donating blood for 6 months and up to 1 year, respectively. It is therefore important to establish whether digestive endoscopy represents a real risk and, if so, to define its magnitude. We conducted a prospective study among outpatients referred to 3 endoscopic units in northwestern Italy from 1999 to 2002. The patients entering the study were tested for antibody to HCV (anti-HCV) at baseline and 6 months after endoscopy. The incidence of HCV infection in this cohort was compared with that in blood donors recruited in the same area and during the same time period; these donors had not undergone any digestive endoscopic procedure. Methods Endoscopy Cohort Between January 1999 and December 2002, all of the outpatients referred for upper digestive endoscopy to 3 endoscopic units in northwestern Italy (1 secondary referral center and 2 tertiary referral centers) were asked to participate in this study. Eligibility criteria were age older than 18 years and indication for gastroscopy. We restricted the procedure to gastroscopy in order to obtain a high rate of invasive procedures (for example, gastric biopsy). We excluded patients if they were hospitalized, had previously undergone endoscopic procedures, were known anti-HCV carriers, or had to undergo additional endoscopic procedures other than gastroscopy. However, to identify the potentially infective population, we retrospectively looked for known HCV carriers who underwent gastroscopy in the 3 centers between January 1999 and December 2002. Of 11348 patients fulfilling the inclusion criteria, 9188 (81.0%) agreed to participate and gave written consent. They completed a questionnaire about risk factors for HCV infection during the past 6 months, and a serum sample was obtained from each immediately before endoscopy. Mild sedation with midazolam and hyoscine butylbromide was administered to each patient by using disposable syringes and vials. Gastroscopies were done by using various types of endoscopes, including fiberscopes and video endoscopes (Olympus GIF-Q20, GIF-Q30, GIF-IT30, GIF-IT140, Olympus Europe, Hamburg, Germany). Biopsies were performed with disposable biopsy forceps (Radial Jaw 3, Boston Scientific Microvasive, Natick, Massachusetts) in one center and reusable biopsy forceps (FB-24U-1, Olympus Europe) in another center; the third center used reusable forceps (EN-62143, Pescetto, Genova, Italy) in 1999 and disposable forceps (Max Capacity, Boston Scientific Microvasive) after 1999. Each patient was invited to attend a follow-up visit 6 months after endoscopy in order to obtain a serum sample for determining anti-HCV; at this visit, the patient was asked to complete the HCV questionnaire again. To reduce the risk for false-negative results, potentially immunodeficient patients (those undergoing hemodialysis or receiving immunosuppressive treatment) were also tested for HCV RNA by polymerase chain reaction (PCR). All patients who did not attend the follow-up visit were recontacted by telephone. Among patients in the endoscopy cohort, we identified an at-risk subset of patients: Overall, 912 endoscopic procedures (732 gastroscopies performed on known HCV carriers and 180 gastroscopies performed on newly discovered HCV carriers) were considered potentially infective. When we considered that each endoscope was used 3 times during the endoscopic session and assumed that the anti-HCVpositive patient was the first, second, or third at random, the number of exposed patients per HCV-infectedpatient-day was 0, 1, or 2, with equal probability (the mean of those numbers is 1). Blood Donors Cohort Using a computerized database, we retrospectively identified all 51645 consecutive blood donors at 2 transfusion centers in Torino and Pinerolo between January 1999 and December 2002 who were negative for HCV. Of these, 415 (0.8%) reported previous digestive endoscopy; the blood bank database did not record invasive procedures performed during endoscopy (such as biopsy and polypectomy). These 415 donors were asked to repeat the serologic and virologic HCV tests: 329 (79.3%) agreed, and 86 declined. Of the 51230 blood donors who did not undergo endoscopic procedures during the observation period, 38 280 (74.7%) were tested again after a mean of 2.49 years (range, 6 months to 4 years); the remaining 12 950 blood donors could not be contacted by telephone for retesting or declined to be retested. Retested blood donors found to be newly positive for anti-HCV completed a structured questionnaire aimed at investigating risk factors for HCV infection, including endoscopic procedures, travel history, sexual activity, and potential parenteral exposures to blood or blood products (previous blood, platelet, or plasma transfusions; administration of coagulation factor concentrates; intravenous drug use; tattooing; acupuncture therapy; ear piercing; and major or minor surgery). Cleaning and Disinfection Method The instruments used for the known HCV carriers were not handled differently from those used for the HCV-negative patients; they were not removed from the general instrument pool, were disinfected in the same way as the others, and were then used promptly to perform endoscopy on the HCV-negative patients. Moreover, endoscopic procedures in known HCV carriers were not postponed at the end of the session but were performed according to the list of scheduled appointments. All units participating in this study adhered to the international guidelines for cleaning and disinfection practices in digestive endoscopy (6-10) and reprocessing endoscopic accessories (11); written protocols were available in each center. The staff involved in disinfection procedures consisted of trained nurses who were unaware of the ongoing study. At the end of the endoscopic procedure, the staff manually cleaned the instrument, including brushing the channels; each internal channel was flushed with detergent, rinsed with water, and blown through with air. The endoscopic units used 3 different automated washer-disinfectors (DSD-91E, Medivators, Minneapolis, Minnesota; Circlean MC-12, Shoei, Tokyo, Japan; and ETD2, Olympus Europe), but the reprocessing cycle was similar: 1) The units were immersed in 2% glutaraldehyde for 20 minutes, and internal channels were flushed with the same solution; 2) the units were rinsed internally and externally with drinking-quality water to remove all traces of disinfectant; and 3) the units were dried externally and each channel was flushed with air. Before the first endoscopy of each day, all endoscopes were disinfected in a washer-disinfector. After use, reusable biopsy forceps were immersed in enzymatic detergent solutions; next, they were cleaned first manually and then by a medical-grade ultrasonic cleaner. After rinsing and drying, the forceps were sterilized by autoclave at 134 C for at least 5 minutes. Finally, the sterilized devices were stored in sterile packaging in a closed cupboard where they were protected from dust, humidity, and temperature fluctuations. Laboratory Methods We tested for anti-HCV by using a third-generation enzyme immunoassay (Ortho HCV EIA-3, Ortho Diagnostic Systems, Raritan, New Jersey). Anti-HCV immunoreactivity was confirmed with a third-generation immunoblot assay (RIBA-3, Chiron Corp., Emeryville, California, and Ortho Diagnostic Systems). We measured HCV RNA by using PCR (Cobas Amplicor 2.0, Roche Diagnostic Systems, Branchburg, New Jersey); the sensitivity of this assay was 1000 copies/mL. Statistical Analysis We estimated person-years of observation and incidence rates of anti-HCV seroconversion for both cohorts. We used the difference between the incidence rates to compare the 2 cohorts. For the endoscopy cohort, we also measured the risk for anti-HCV seroconversion 6 months after the procedure, using the number of persons as denominators. Further analyses were limited to subgroups of the endoscopy cohort: 1) 6132 patients who underwent biopsy (biopsy cohort) and 2) 912 patients who underwent endoscopy later in the same day as and with the same instruments used in HCV-positive patients (at-risk cohort). Because we could not identify with certainty each patient in the at-risk cohort, we estimated that number with a rough but conservative approach. If we assume that each endoscope was used approximately 3 times during an ordinary endoscopic session and that at least 1 HCV carrier would be seen at

Epidemiology of hepatitis D.

Hepatitis D occurs worldwide. The major victims of the hepatitis D virus (HDV) are individuals carrying the hepatitis B surface antigen (HBsAg); around 5% of the HBsAg carriers in the world are infected also by HDV. With the implementation of a hepatitis B virus (HBV) vaccination since the 1990s, the incidence of hepatitis D has consistently declined in the developed world, particularly in Southern Europe; however, immigrants from areas where HDV remains endemic are reintroducing the infection.Hepatitis D continues to ravage populations of developing and poor countries where HBV remains unchecked; action is needed to enforce HBV vaccination as effective prophylaxis not only against HBV, but against HDV as well.

Outcome of chronic delta hepatitis in Italy: a long-term cohort study.

BACKGROUND & AIMS To investigate the impact of HDV infection on morbidity and mortality of patients. PATIENTS AND METHODS This was a retrospective study on 188 patients that underwent a program of periodic surveillance until 2008. The demographic data, stage of liver disease, treatment efficacy, development of liver complications (ascites, oesophageal bleeding, encephalopathy), and survival were registered. A Cox regression analysis was carried out to determine the impact of viral and patient features on survival. RESULTS At baseline, 126 patients (67%) tested positive for serum IgM anti-HDV antibodies, 171 (91%) for anti-HBe, 175 (93%) for serum HDV-RNA, and 61 (33%) for serum HBV-DNA. Eighty-two patients (43%) had chronic hepatitis at histology; the remaining 106 individuals had a clinical/histological diagnosis of cirrhosis. Ninety-six patients received interferon (n = 90) or lamivudine (n = 6) therapy, and 27 of them (30%) attained a sustained response. During follow up, 21 patients with chronic hepatitis progressed to cirrhosis. Of the 127 cirrhotic patients, hepatic decompensation occurred in 42 patients (33%) and hepatocellular carcinoma in 17 (13%). The 5- and 10-year survival free of events were 96.8% and 81.9%, respectively, for patients with chronic hepatitis, and 83.9% and 59.4% for cirrhotics (p<0.01). At multivariate analysis, lack of antiviral therapy (p = 0.01), cirrhosis at presentation (p<0.01), and male sex (p = 0.03) independently predicted a worse outcome. CONCLUSION HDV liver disease lasts several decades. Half of all patients who develop cirrhosis later will advance to liver failure. At present, interferon therapy is recommended as soon as possible to slow or alter the natural course of liver disease.

Hepatitis B virus (HBV) DNA integration in patients with occult HBV infection and hepatocellular carcinoma

Hepatitis B virus (HBV) DNA integration in the host genome is a major mechanism responsible for the etiopathogenetic role exerted by HBV in hepatocellular carcinoma (HCC) development. Extensive analyses evaluating viral integration in HBV surface antigen (HBsAg) negative patients with occult HBV infection (OBI) have not yet been performed. The aim of this study was to investigate and characterize HBV DNA integration in HCC tissues from OBI patients.