Antonina Smedile

IL28B is associated with response to chronic hepatitis C interferon-alpha and ribavirin therapy

Hepatitis C virus (HCV) infects 3% of the worlds population. Treatment of chronic HCV consists of a combination of PEGylated interferon-α (PEG-IFN-α) and ribavirin (RBV). To identify genetic variants associated with HCV treatment response, we conducted a genome-wide association study of sustained virological response (SVR) to PEG-IFN-α/RBV combination therapy in 293 Australian individuals with genotype 1 chronic hepatitis C, with validation in an independent replication cohort consisting of 555 individuals. We report an association to SVR within the gene region encoding interleukin 28B (IL28B, also called IFNλ3; rs8099917 combined P = 9.25 × 10−9, OR = 1.98, 95% CI = 1.57–2.52). IL28B contributes to viral resistance and is known to be upregulated by interferons and by RNA virus infection. These data suggest that host genetics may be useful for the prediction of drug response, and they also support the investigation of the role of IL28B in the treatment of HCV and in other diseases treated with IFN-α.

STATEMENTS FROM THE TAORMINA EXPERT MEETING ON OCCULT HEPATITIS B VIRUS INFECTION

Giovanni Raimondo*, Jean-Pierre Allain, Maurizia R. Brunetto, Marie-Annick Buendia, Ding-Shinn Chen, Massimo Colombo, Antonio Craxi, Francesco Donato, Carlo Ferrari, Giovanni B. Gaeta, Wolfram H. Gerlich, Massimo Levrero, Stephen Locarnini, Thomas Michalak, Mario U. Mondelli, Jean-Michel Pawlotsky, Teresa Pollicino, Daniele Prati, Massimo Puoti, Didier Samuel, Daniel Shouval, Antonina Smedile, Giovanni Squadrito, Christian Trepo, Erica Villa, Hans Will, Alessandro R. Zanetti, Fabien Zoulim

INFLUENCE OF DELTA INFECTION ON SEVERITY OF HEPATITIS B

The prevalence of serum markers of primary delta infection was determined in 532 patients with acute benign hepatitis B seen in Italy, and in 111 patients with fulminant hepatitis B seen in Italy, France and England. Patients with fulminant hepatitis had significantly higher prevalence of delta markers (43/111, 39%) than did those with benign hepatitis (101/532, 19%). In 25 of the 43 patients with delta-positive fulminant hepatitis, serum markers indicated a primary hepatitis B infection while in the remaining 18, IgM antibody to hepatitis B core antigen was absent, indicating that hepatitis B preceded superinfection with the delta agent. The increased morbidity of HBsAg hepatitis with delta infection may result from the cumulative simultaneous exposure to hepatitis B virus and delta, or from superinfection of HBsAg carriers with delta.

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.

IL28B, HLA-C, and KIR variants additively predict response to therapy in chronic hepatitis C virus infection in a European Cohort: a cross-sectional study.

Vijayaprakash Suppiah and colleagues show that genotyping hepatitis C patients for the IL28B, HLA-C, and KIR genes improves the ability to predict whether or not patients will respond to antiviral treatment.

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.)

Longitudinal evaluation reveals a complex spectrum of virological profiles in hepatitis B virus/hepatitis C virus–coinfected patients†‡

Hepatitis B virus (HBV) and hepatitis C virus (HCV) coinfection is often associated with severe forms of liver disease. However, comprehensive studies are lacking, and scant information is available regarding the virological behavior over time in coinfected patients. This study enrolled 133 untreated HBV/HCV‐positive patients (male/female = 102/31; median age 51 years [range: 22‐83 years]) who were longitudinally followed up for 1 year with bimonthly evaluation of HBV/HCV viremia levels and liver biochemistry. Thirty of these patients had triple infection with hepatitis Delta virus (HDV), while 103 patients were HDV‐negative. In the HDV‐negative group, active infection with both HBV and HCV was revealed in 24 cases, inactive infection by both viruses was seen in 15 cases, active HBV/inactive HCV was seen in 15 cases, and inactive HBV/active HCV was seen in 49 cases. However, 32 subjects (31%) presented dynamic virological profiles characterized by fluctuation of HBV and/or HCV viremia levels that at different time points were over or under the cutoff limits. Consequently, a correct diagnosis could be performed in these subjects only by serially repeating the virological tests 1 year apart. Similarly, 15 of the 30 HDV‐positive subjects showed active HBV and/or HCV infection, with fluctuating virological patterns in 8 cases. In conclusion, this study showed that the virological patterns in HBV/HCV coinfection are widely divergent and have dynamic profiles. A careful longitudinal evaluation of the viremia levels of both viruses is essential for making a correct diagnosis and tailoring the appropriate therapeutic schedule in coinfected patients. (HEPATOLOGY 2005.)

Reliability of transient elastography for the detection of fibrosis in Non-Alcoholic Fatty Liver Disease and chronic viral hepatitis

BACKGROUND & AIMS Transient elastography (TE) is validated in chronic hepatitis C (CHC) to evaluate hepatic fibrosis; however, limited data are available in chronic hepatitis B (CHB) and non-alcoholic fatty liver disease (NAFLD). This prospective study is aimed to assess the accuracy and the efficacy of TE for the detection of fibrosis in patients with chronic liver disease of different etiology and to evaluate the effect of steatosis on the liver stiffness measurement (LSM). METHODS TE was performed in 219 consecutive patients with chronic liver disease (35% CHC, 32% CHB, and 33% NAFLD) within 6 months of the liver biopsy. RESULTS LSM was related to the fibrosis stage in each group (CHC: p = 0.596, p < 0.001; CHB: p = 0.418, p < 0.001; NAFLD: p = 0.573, p < 0.001), but the correlation was less strong in CHB and NAFLD than in CHC patients. In CHB patients with histological cirrhosis (F4), the median stiffness value was almost two times lower than in patients with severe fibrosis (F3). In NAFLD patients with advanced fibrosis (F3) and severe steatosis (> 33%), the LSM values were lower than expected and were similar to those of patients with initial fibrosis (F1) and fat < 33%. TE underestimated the stage of fibrosis in 75% of patients with F3 and steatosis > 33%. At multiple logistic regression analysis, in CHC and CHB patients, LSM was the only predictive variable of severe fibrosis/cirrhosis (OR = 1.42, p = 0.003 and OR = 1.354, p = 0.003, respectively), while in NAFLD subjects BMI and AST (OR = 1.433, p = 0.002 and OR = 1.053, p = 0.020, respectively) but not LSM were independently related with advanced fibrosis and cirrhosis. CONCLUSIONS This study confirms that TE can be considered a valid support to detect fibrosis in chronic liver disease related to HCV but it should be interpreted cautiously in CHB and NAFLD patients, where host or disease-related factors may modify its accuracy.

Infection with the delta agent in chronic HBsAg carriers

To establish the mechanism of progression to chronicity of the HBsAg-associated delta infection, serum hepatitis B virus and delta markers were tested in five babies born to HBsAg-positive mothers with anti-delta, in 42 follow-up patients with acute hepatitis B virus and delta hepatitis, and in collections of sera from 8 HBsAg carriers with anti-delta. Evidence of delta infection was found in the baby born to a mother with serum HBeAg and in none of the four babies born to mothers with anti-HBe. Hepatitis was self-limited in the 42 patients acutely infected by hepatitis B virus and delta agent; none developed persistent HBs-antigenemia and the majority displayed transient anti-delta of IgM class. In seven HBsAg carriers high titers of anti-delta developed during the follow-up; coincident with the rise of the antibody, aminotransferase elevation occurred in five previously asymptomatic carriers and persisted in three of them. No sign of infectious hepatitis B virus replication was detected in five of the carriers throughout the follow-up, and all of them had anti-HBe before the rise of anti-delta and of aminotransferase. HBsAg carriers with diminished hepatitis B virus synthesis appear to be at high risk of developing chronic delta infection and disease when exposed to the delta-infectious serum of other carriers.

Multicentre study of prevalence of HBV-associated delta infection and liver disease in drug-addicts.

To assess the epidemiological and pathogenic effects of infection with the hepatitis-B-virus (HBV)-associated delta agent in addicts who take drugs parenterally, 225 symptomless addicts from Italy and 261 addicts with HBsAg-positive hepatitis from Italy, Denmark, Switzerland, and Ireland were tested for delta antigen (delta-Ag) and its antibody (anti-delta) by radioimmunoassay. 79 liver biopsy specimens from HBsAg-positive addicts were also tested for intrahepatic delta-Ag by immunofluorescence. Anti-delta was found in 9 (27%) of 33 of the symptomless HBsAg-positive addicts, in 13 (8%) of 156 of those without HBsAg but with anti-HBs, and in none of those negative for HBV markers. The prevalence of serum delta-Ag or anti-delta among addicts with HBsAg-positive hepatitis was 64% (104/161) in Italy, 44% (8/18) in Denmark, 33% (11/33) in Switzerland, and 31% (15/49) in Ireland. 32 of the 79 (40%)liver biopsy specimens from HBsAg-positive addicts showed positive delta-Ag immunofluorescence. Delta infection occurring simultaneously with HBV infection is common and possibly a major cause of liver disease in drug addicts who receive drug parenterally. The spread of delta infection in drug-using communities is not confined to one country, and the drug habit may represent the major means by which delta agent spreads in areas of the Western world where this infection is not endemic.