Donatella Ferraro

Hepatitis B virus reactivation and alemtuzumab therapy

Abstract:  Reactivation of hepatitis B virus infection in subjects receiving cytotoxic treatment for heamatological malignancies occurs in 21–53% of chronic HBsAg carriers and in an unknown number of HBsAg negative subjects harbouring occult HBV infection. Immunotherapy with alemtuzumab, a humanized monoclonal antibody against CD52 epitopes on lymphocytes cells produces deep immunosuppression. We describe two subjects with chronic lymphocytic leukaemia and occult HBV infection who developed a virological and biochemical flare of hepatitis B following immunotherapy with alemtuzumab. One of them developed full blown hepatitis with seroreversion from anti‐HBs to HBsAg after four weeks of alemtuzumab therapy. Lamivudine (100 mg die) achieved a complete clinical recovery and HBV‐DNA clearance from blood within 8 weeks. The second patient (HBsAg and HBV‐DNA seronegative, anti‐HBs and anti‐HBc positive before treatment) was kept under prophylaxis with lamivudine up to three months after alemtuzumab. Two months after withdrawal of lamivudine, clinical and laboratory features of acute hepatitis B developed. Lamivudine therapy was restarted and a prompt recovery was obtained with HBsAg and HBV‐DNA clearance.

IL-10 and TNF-α polymorphisms and the recovery from HCV infection

Abstract Hepatitis C virus (HCV) infection becomes chronic in about 85% of infected individuals, whereas only 15% of infected people clear spontaneously the virus. It is conceivable that the host immunogenetic background influences the course of infection in term of recovery. Thus, in this study we have evaluated the effect of functionally relevant polymorphisms at tumor necrosis factor-α (TNFα, i.e., 2 biallelic polymorphisms at nt -863 and nt-308 of the promoter) and interleukin-10 (IL-10) loci (i.e., 1 biallelic polymorphism at nt -1082 of the promoter), on the clearance of HCV infection. To this purpose, we compared 18 Sicilian patients who had spontaneously recovered from previous HCV infection with 42 Sicilian patients with current HCV infection and 135 Sicilian healthy patients. The results demonstrate a decreased frequency of the -863CC TNF-α promoter genotype (involved in high production of this pro-inflammatory cytokine) and an increased frequency of the -1082GG IL-10 promoter genotype (involved in high production of this anti-inflammatory cytokine) in patients recovered from HCV infection. The evaluation of combined TNF-α and IL-10 genotypes revealed a significant increase of the “anti-inflammatory genotype” (low-TNF/high-IL-10 producers) in resolved HCV infection group compared with patients with persistent HCV infection. On the whole, our findings suggest that a genetically determined control of the HCV-induced inflammatory response may play a role in the resolution of HCV infection.

The impact of insulin resistance, serum adipocytokines and visceral obesity on steatosis and fibrosis in patients with chronic hepatitis C

Aims  To assess whether host metabolic factors influence the degree of hepatic steatosis and fibrosis in patients infected with hepatitis C virus, and to evaluate the impact of anti‐viral therapy on insulin resistance and serum levels of adipocytokines.

Distribution of VP7 serotypes and VP4 genotypes among rotavirus strains recovered from Italian children with diarrhea

Summary108 rotavirus strains obtained from children with diarrhea hospitalized in Palermo, Italy, in the years 1990–1994, were examined by seminested PCR to study the relative frequency and distribution of the four most common alleles of the gene 4. Such strains were selected from 344 human rotavirus strains recovered in Palermo during those years after characterization by electropherotyping, subgrouping and G serotyping. One hundred and seven of the 108 strains could be classified into P types, the P[8], G1 (38.3%) and the P[8], G4 (52.3%) types being predominant. The unique strain whose P genotype could not be identified showed an unusual combination of long migration electrophoretic pattern and subgroup I specificity.

Hepatic steatosis and insulin resistance are associated with severe fibrosis in patients with chronic hepatitis caused by HBV or HCV infection.

Background and aims: Steatosis and insulin resistance (IR) are the major disease modifying in patients with chronic hepatitis C (CHC). Only few studies evaluated these features in patients with chronic hepatitis B (CHB). We aimed to assess the prevalence and the factors related to steatosis and IR in CHB patients, compared with CHC subjects, and to evaluate the potential association between these features and fibrosis severity.

Combined treatment of relapse of chronic hepatitis C with high-dose α2b interferon plus ribavirin for 6 or 12 months

BACKGROUND/AIMS Retreatment of relapses of chronic hepatitis C with a standard regimen of interferon plus ribavirin for 6 months obtains a sustained response in a minority of patients with high viraemia and genotype 1b. We aimed to assess whether increasing the interferon dose and prolonging the time of combined treatment may enhance the effectiveness, and also to evaluate the tolerability, and to identify the determinants of sustained response. METHODS Fifty subjects with chronic hepatitis C who had relapsed after one or more courses of a-interferon monotherapy were randomised to receive alpha2b interferon (6 MU tiw) plus ribavirin (1000-1200 mg daily) for 6 or 12 months. ALT normalisation and serum HCV-RNA clearance at the end of treatment and 6 months after stopping therapy were used as markers for sustained response. RESULTS End-of-treatment response was achieved in 48 patients (96%) and 27 (54%) had a complete sustained response. Patients treated for 12 months had a higher rate of sustained response (18/25, 72%; 95% C.I. 0.54-0.89) than those treated for 6 months (9/25, 36%; 95% C.I. 0.17-0.55, p=0.01). Twelve months of therapy was significantly more effective for patients with genotype 1b and baseline serum HCV-RNA greater than 450 000 copies/ml (p=0.005). Seven subjects (14%) discontinued treatment because of side effects. Logistic regression analysis showed 12 months of therapy, young age and low pre-treatment serum HCV-RNA to be independent predictors of sustained response. CONCLUSIONS Relapsers with genotype 1b and high levels of HCV-RNA will benefit from a 12-month course of 6 MU tiw interferon plus ribavirin, while subjects with genotype 1b and low levels of serum HCV-RNA or with genotype other than 1b may be treated for 6 months.

Formulation of a novel synthetic medium for selectively culturing rat CNS neurons

Dissociated cells from rat fetal cerebral hemispheres were grown in surface adhering culture using a novel synthetic medium (Maat medium) and compared with those grown either in the presence of serum or in the chemically defined medium described by Bottenstein and Sato. The addition of various compound combinations allowed us to lower insulin concentration to almost physiological levels. Maat medium improved the purity and longevity of neuronal cultures. The purity of neuronal cultures grown in different media was checked both by immunofluorescence and by the analysis of [3H]thymidine incorporation.

Liver disease in chelated transfusion-dependent thalassemics: the role of iron overload and chronic hepatitis C

This study shows that hepatitis C virus infection is the main risk factor for liver fibrosis in chelated transfusion-dependent thalassemic patients. See related perspective article on page 1121. Iron overload and hepatitis virus C infection cause liver fibrosis in thalassemics. In a monocentric retrospective analysis of liver disease in a cohort of 191 transfusion-dependent thalassemics, in 126 patients who had undergone liver biopsy (mean age 17.2 years; 58 hepatitis virus C-RNA positive and 68 hepatitis virus C-RNA negative) the liver iron concentration (median 2.4 mg/gr dry liver weight) was closely related to serum ferritin levels (R = 0.58; p<0.0001). Male gender (OR 4.12) and serum hepatitis virus C-RNA positivity (OR 11.04) were independent risk factors for advanced liver fibrosis. The majority of hepatitis virus C-RNA negative patients with low iron load did not develop liver fibrosis, while hepatitis virus C-RNA positive patients infected with genotype 1 or 4 and iron overload more frequently developed advanced fibrosis. Hepatitis virus C infection is the main risk factor for liver fibrosis in transfusion-dependent thalassemics. Adequate chelation therapy usually prevents the development of liver fibrosis in thalassemics free of hepatitis virus C-infection and reduces the risk of developing severe fibrosis in thalassemics with chronic hepatitis C.

Identification of picobirnavirus from faeces of Italian children suffering from acute diarrhea

Polyacrylamide gel electrophoresis of nucleic acid extracted from stool samples of diarrhoeic children revealed in 3 out of 690 (0.43 %) specimens two electrophoretic bands with a migration pattern characteristic of picobirnavirus ds-RNA. In none of the 92 control children were similar bands detected. No other potential enteric pathogens were found in the patients with picobirnavirus infection.

Vitamin D levels and IL28B polymorphisms are related to rapid virological response to standard of care in genotype 1 chronic hepatitis C

BACKGROUND Genotype 1 (G1) chronic hepatitis C (CHC) patients achieving a rapid virological response (RVR) on pegylated interferon (PEG-IFN) plus ribavirin have a high chance of sustained virological response (SVR), influenced by IL28B status, viral load, fibrosis and insulin resistance. We assessed whether 25-hydroxyvitamin D (25[OH]D) serum levels are linked to RVR and can be used together with IL28B to construct a pretreatment model to predict RVR. METHODS A total of 117 consecutive patients with G1 CHC were evaluated by biopsy and anthropometric and metabolic measurements. 25(OH)D serum levels were measured by HPLC. IL28B rs12979860 and rs8099917 polymorphisms were also evaluated. All patients underwent antiviral therapy with PEG-IFN-α2a plus ribavirin. HCV RNA was assessed at baseline, week 4, week 12, at the end of therapy and after 6 months of follow-up. RESULTS Mean ±SD 25(OH)D serum levels were 26.3 ±10.6 μg/l (range 8.0-58.0) and 31 (26.5%) patients had the rs12979860 CC polymorphism. RVR was achieved in 35 (29.9%) patients, and 32 (91.4%) of them had an SVR, compared to 26 of 82 (31.7%) without RVR. The rs12979860 CC polymorphism (OR 4.575, 95% CI 1.761, 11.889; P=0.002) and higher 25(OH)D levels (OR 1.055, 95% CI 1.010, 1.101; P=0.01) were independently associated with the achievement of RVR by multivariate analysis. The likelihood of RVR progressively increased from patients in the worst class (vitamin D<26.8 μg/l and TT/TC polymorphism; RVR 14.2%), to those with only one positive predictor (RVR 29.7% and 37.5%), and to those in the best class (vitamin D≥26.8 μg/l and rs12979860 CC polymorphism; RVR 73.3%). CONCLUSIONS In patients with G1 CHC, 25(OH)D serum levels and IL28B status are independently associated with the likelihood to achieve RVR and SVR. When incorporated into a pretreatment predictive model they can assist in further discriminating patients with a high likelihood of achieving RVR and SVR.