Antonella Olivero

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.)

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

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

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.

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.

Four years of treatment with lamivudine: clinical and virological evaluations in HBe antigen-negative chronic hepatitis B.

Aim : To evaluate the clinical and virological impact of the prolonged use of lamivudine in 94 patients with HBe antigen‐negative chronic hepatitis B.

Lamivudine-resistant chronic hepatitis B: An observational study on adefovir in monotherapy or in combination with lamivudine ☆

BACKGROUND/AIMS In lamivudine-resistant patients with chronic hepatitis B (CHB), we compared efficacy, predictive response factors and changes in viral mutants in two antiviral approaches with adefovir. METHODS A prospective cohort study on therapy with adefovir alone (29 patients) or combined with ongoing lamivudine (23 patients) was performed. RESULTS A virological response was achieved in 55% of patients treated with adefovir and in 83% of those treated with the combination (p>0.05). This response was directly related to the basal viral load (p<0.0001) and obtained in 10 patients with basal HBV-DNA<17,200 IU/ml using both strategies. In patients with a higher basal viral load, the virological response was more frequent when treated with the combination (p<0.05). Mutation at locus rt181 predicted HBV-DNA persistence during therapy. A virological rebound was observed in 18% of non-responders while on adefovir monotherapy. CONCLUSIONS To achieve a complete virological response and reduce the risk of adefovir-resistant mutants in lamivudine-resistant patients, rescue therapy is preferable at early evidence of genotypic resistance. However, in subjects with a significant viral load, combination therapy is more effective. The presence of the rt181 mutation is associated with incomplete response.

Hepatitis delta virus diagnosis.

The first step in the diagnosis of hepatitis delta virus (HDV) infection is testing HBsAg-positive individuals for the antibody to the HD antigen (anti-HD).In anti-HD-positive patients, the next step is testing for HDV RNA in serum to determine whether the antibody reflects an ongoing active HDV infection (HDV-RNA-positive) or represents a serologic scar to past HDV infection (HDV-RNA-negative). In the HDV-positive individual with liver disease, it is critical to distinguish acute HDV/hepatitis B virus (HBV) coinfection from chronic HDV superinfection in HBsAg carriers; the course, prognosis, and management of the two conditions are different. The differential diagnosis can be achieved through the scrutiny of the battery of HDV and HBV markers, which combine in patterns characteristic for each condition.Standardized competitive and μ-capture commercial assays are available to determine the IgG and IgM antibody to HDV. Several in-house assays were developed to determine HDV RNA in serum; the sensitivity threshold of current polymerase chain reaction-based assays is 10 copies of HDV RNA/mL. Unfortunately, HDV-RNA assays are not yet standardized and the results from different laboratories often are not comparable due to different sensitivities. The development of an international reference HDV-RNA standard remains an unmet diagnostic need.

IL28B polymorphism genotyping as predictor of rapid virologic response during interferon plus ribavirin treatment in hepatitis C virus genotype 1 patients

AIM To clarify the association of interleukin-28B (IL28B) single nucleotide polymorphisms (SNPs) with hepatitis C virus (HCV) viremia changes for assessment of interferon (IFN) response. METHODS A cohort of 118 Caucasian treatment-naïve HCV-G1 infected patients, treated with pegylated-IFN alpha 2a or 2b associated with ribavirin (53 responders, 65 non-responders) during the period 2010-2012, were genotyped for IL28B SNPs rs12979860 C>T and rs8099917 T>G. Genotyping was performed by real-time allelic discrimination assay. Serum HCV RNA levels were assayed at 2, 4, 12, 24 and 48 wk during therapy. Correlation between IL28B genotypes and serum HCV RNA kinetics was investigated. Multivariable logistic regression analysis was performed to identify predictors of null-response. RESULTS Twenty-six out of 118 patients (22%) had no HCV RNA decline ≥ 1 log IU/mL at therapy week 4 (null-responders). IL28B genotype was rs8099917 (G)/rs1297860 in 21/26 (80%) of null-responder patients. Using multivariate analysis, it was shown that the presence of the rs8099917 G allele was the best predictor of null-response (OR = 7.9, 95%CI: 1.99-31.18). The presence of at least one favorable genotype showed a positive predictive value of above 90% for HCV RNA reduction ≥ log at week 4. Analysis of the HCV RNA kinetics during 12 wk of therapy in patients with IL28B rs12979860 CT heterozygosis (n = 73), according to their rs8099917 status, showed that the viremia reduction was significantly different in patients carrying the rs8099917 G allele compared to those with favorable homozygosis. CONCLUSION Our findings emphasize the association of the IL28B rs8099917 G allele with HCV. Genotyping for both IL28B SNPs is useful in clinical practice for thorough patient risk stratification based on IFN responsiveness.

Cytoskeletal modifications induced by 4-hydroxynonenal

The antiproliferative action of 4-hydroxynonenal (HNE) could be related to an interaction with cytoskeletal structures. In this paper the effects exerted by HNE on microtubules and on microfilaments are examined by immunofluorescence. HNE alters cell morphology causing both the depolymerization of the microtubular structures and the dissolution of the stress-fibres. Taxol protects microtubules, preventing the depolymerizing effect of the aldehyde. The action of HNE could be attributed to its affinity for sulphydryl groups, which are essential in maintaining tubulin and actin both in the polymerized form.

Quantification of hepatitis B surface antigen with the novel DiaSorin LIAISON XL Murex HBsAg Quant: correlation with the ARCHITECT quantitative assays.

BACKGROUND Recent technologic innovations allow for quantitative assessment of hepatitis B surface antigen (HBsAg) levels in serum; this has been used to monitor the course of chronic HBV hepatitis (CHB) and predict treatment response. LIAISON-XL Murex HBsAg Quant assay (DiaSorin, Saluggia, I) is the newest immunoassay CE approved to quantify HBsAg. OBJECTIVES To compare LIAISON-XL performances with ARCHITECT-QT HBsAg (Abbott Diagnostics, IL, USA), as reference test. STUDY DESIGN Sequential serum samples (n=152) from 14 HBe-negative patients with CHB, the majority of them infected by HBV genotype D undergoing antiviral treatment, were retrospectively tested with both assays. The 2nd WHO Standard 00/588 for HBsAg was used as reference. RESULTS LIAISON-XL and ARCHITECT-QT correlated by r=0.95, p<0.0001; by Bland-Altman analysis agreement of mean difference was 0.21 ± 0.15 log 10 IU/mL, 95% CI: -0.07 to 0.5). Performance of LIAISON-XL against the 2nd WHO Standard was r=0.998, p<0.0001 (95% CI: 0.993-0.999) with results nearer to the expected WHO values compared to ARCHITECT-QT. Median baseline HBsAg level was similar with the two methods before antiviral treatment, throughout fluctuations of HBsAg level in treatment non-responders and during the decrease of HBsAg titer in treatment responders. Correlation between HBsAg levels and HBV DNA was statistically significant for both the two immunoassays (LIAISON-XL: r=0.4988, 95% CI: 0.3452-0.6264, p<0.0001; ARCHITECT-QT: r=0.480, 95% CI: 0.3233-0.6111, p<0.0001). CONCLUSIONS Correlation between HBsAg measurement with LIAISON-XL and ARCHITECT-QT was high. LIAISON-XL accurately quantified HBsAg in clinical samples at baseline or during antiviral therapy; it can be applied for HBsAg quantification in clinical practice and decision making in CHB.