Gene therapy approaches in chronic viral hepatitis

The clinical and socioeconomic background of chronic viral hepatitis is favourable to new therapeutic approaches based on gene biochemistry. As with all gene therapy, the treatment of chronic viral hepatitis using this approach would make use of a therapeutic gene and a delivery system adapted to the pharmaceutical objectives of targeting, gene expression and kinetics. The various vectors under review are not yet sufficiently optimized for selective targeting of infected hepatocytes. Moreover, four therapeutic gene processes are currently under development: antisense oligonucleotides, ribozymes, dominant negative mutants and DNA vaccines. These developments are obviously limited by the lack of experimental or animal models representative of the pathophysiology of chronic viral hepatitis. The gene therapy for chronic viral hepatitis is nearly ready for clinical evaluation but must be weighed against the continuous progress of pharmaceutical treatments.     

T-regulatory lymphocytes and chronic viral hepatitis

Both hepatitis B virus (HBV) and hepatitis C virus (HCV) can cause persistent viral infection in humans. Chronic infection is associated with a risk of cirrhosis and hepatocellular carcinoma. The cause of chronic infection is unknown. A large body of evidence suggests that a failure of the adaptive immune response is critical in the establishment of chronic infection. Recently a new group of T cells (T-regulatory cells), that express CD4(+)CD25(+) and Foxp3, which can inhibit the cellular (CD4(+)/CD8(+)) immune response have been described. In this review the authors explore the thoughts regarding immune responses to HBV and HCV infections and the role of these T-regulatory cells in relation to the pathogenesis of chronic HBV and HCV infection and the potential for therapeutic intervention.     

T-regulatory lymphocytes and chronic viral hepatitis

Both hepatitis B virus (HBV) and hepatitis C virus (HCV) can cause persistent viral infection in humans. Chronic infection is associated with a risk of cirrhosis and hepatocellular carcinoma. The cause of chronic infection is unknown. A large body of evidence suggests that a failure of the adaptive immune response is critical in the establishment of chronic infection. Recently a new group of T cells (T-regulatory cells), that express CD4⁺CD25⁺ and Foxp3, which can inhibit the cellular (CD4⁺/CD8⁺) immune response have been described. In this review the authors explore the thoughts regarding immune responses to HBV and HCV infections and the role of these T-regulatory cells in relation to the pathogenesis of chronic HBV and HCV infection and the potential for therapeutic intervention.     

Treatment of chronic viral hepatitis.

Significant advances have been made in the treatment of both hepatitis B and C. Cure for the majority is becoming reality. Combination regimens are now established therapy in hepatitis C and the near future will see the adoption of a similar approach to hepatitis B. Interferon alpha therapy remains important, with the development of more efficacious pegylated forms. In this article we review current therapy and discuss future strategies of the therapy for chronic viral hepatitis.     

Interleukins in chronic diseases of digestive organs

AIM: To characterize quantitatively and functionally interleukines (IL) in chronic gastrointestinal diseases (CGD) depending on the affected organ, etiology, activity and stage of the disease. MATERIAL AND METHODS: Levels of IL-1 beta, IL-4, IL-6, IL-8, tumor necrosis factor alpha (TNF-alpha), gamma interferon (Inf-gamma) in peripheral blood of 300 patients with chronic hepatitis, gastroduodenal ulcer, cholelithiasis, glutenic enteropathy and other CGD were measured by enzyme immunoassay. RESULTS: CGD are accompanied by cytokine imbalance the severity of which depended on the etiological factor (virus, alcohol, etc.), the disease activity, stage and kind of IL. A maximal IL rise was seen in exacerbations of ulcer, cholelithiasis, chronic viral, autoimmune diseases. At early disease stages higher were the levels of Inf-gamma, IL-1 beta, IL-8, IL-6; at late stages--of TNF-alpha, IL-4. In patients with highly and moderately active CGD content of IL reached 250-750 pg/ml that is 3-5 times higher than in inactive CGD. In alcohol-induced CGD and metabolic disturbances IL level was under 150 pg/ml. CONCLUSION: Assessment of the cytokine spectrum in CGD holds prognostic importance as this spectrum allows conclusion on the disease activity, its progression.     

Hepatocellular carcinoma: clinical and radiological findings in patients with chronic B viral hepatitis and chronic C viral hepatitis

Aim

To compare clinical and radiological findings of newly diagnosed hepatocellular carcinomas (HCCs) in patients with chronic hepatitis B virus (HBV) and chronic hepatitis C virus (HCV) infections.

Materials and Methods

Dynamic contrast-enhanced CT images in 532 patients with newly diagnosed HCC were retrospectively reviewed. Of these patients, 418 had chronic HBV infections and 114 had chronic HCV infections. The number, size, shape (nodular vs. non-nodular) and enhancement pattern (typical vs. atypical) of hepatic lesions were assessed. The presence of portal vein thrombosis and bile duct invasion were determined.

Results

The mean age of the HBV group (54.31 [range 27–85], median 54) was younger than that of the HCV group (64.21 [range 30–86], median 64) (P?5; P?P?=?0.023); non-nodular shape (P?P?=?0.047), association with portal vein thrombosis (P?=?0.004); association with bile duct invasion (P?Conclusions Clinical and radiological findings of HCC differ between patients with HBV and HCV infections.     

Somatopsychic manifestations in patients with chronic viral hepatitis

The aim of the work was to study somatopsychic manifestations in patients with chronic viral hepatitis (CVH). MMPI profiles, state and trait anxiety were assessed in 110 patients. Boundary psychic problems were evaluated using the Beck scale. It was shown that mean MMPI T-score in patients with CVH was above 50; half of them developed "neurotic triad"; hypochondria occurred in 37.3%, depression in 42.7%, and hysteria in 37.1%. The highest level of state anxiety was documented in patients with HCV infection and isolated HBCor At. The CVH-1b genotype was associated with enhanced occurrence of depression in patients having virus-positive blood for 1-5 years. The level of state and trait anxiety in them was lower than in patients with duration of viremia over 5 years.     

Immunogenetic HLA markers of chronic viral hepatitis

AIM: To study possible immunogenetic HLA markers of chronic viral hepatitides. MATERIAL AND METHODS: Using the reaction of complement-dependent cytotoxicity by Terasaki, we analysed distribution of leukocytic HLA antigens (loci A, B and C) in 179 patients with chronic viral hepatitides B, C and D in Russians and Kazakhs living in the Astrakhan Region. RESULTS: In the Russian population we discovered a significant positive association of CVHB with HLA-B18, HLA-B35, HLA-B40, HLA-Cw3 antigens, and negative one--with HLA-A2. In Kazakhs with CVHB there was a positive association with HLA-A3, HLA-B18 and negative one--with HLA-A11. Alleles HLA-A10, HLA-B35, HLA-B40 and HLA-Cw3 mark CVHC in Russians. HLA-Cw4 specificity acts as protector in development of chronic HCV-infection. A correlation was found between carriage of some specificities and haplotypes of HLA and activity of chronic HBV and HCV infection. A high risk of chronic delta infection in Russians is associated with HLA-B8 and HLA-B35, in Kazakhs--with HLA-B35 and HLA-D40. There are significant associations between CVHB, CVHC, chronic delta infection and some HLA haplotypes. CONCLUSION: A universal role of HLA-B35 specificity in development of CVH irrespective of hepatotropic virus and patients' nationality is shown.     

Management of chronic viral hepatitis in the hematological patient

Introduction: Infection with HBV and HCV represents a growing challenge in the management of patients with hematological malignancies. Recently, hepatitis E (HEV) was recognized as an endemic infection in developed countries and as an emerging health problem in immunocompromised patients.

Areas covered: We reviewed the current knowledge on the impact of chronic viral hepatitis in the hematological setting. Epidemiological features, screening strategies and indications for treatment and monitoring have been explored and commented.

Expert commentary: Knowing patient’s complete HBV serostatus is mandatory in order to choose between treatment, prophylaxis or a pre-emptive approach. Recent guidelines favor treatment with high barrier molecules in all patients with chronic HBV infection and long lasting prophylaxis with those with inactive or resolved one. With regard to HCV, the new direct-acting antiviral agents have been safely administered in the hematological setting. Their use as first-line single treatment in indolent lymphomas, and combined with chemotherapy in aggressive ones, should be considered. Due to the existing risk of chronic HEV infection in the immunocompromised, screening with serum HEV-RNA should be performed in case of signs and symptoms indicative of hepatitis. In the event of HEV infection, reduction of immunosuppression and, if not feasible or unsuccessful, ribavirin treatment should be prescribed.     

"Hematological masks" of chronic viral hepatitis

AIM: To reveal the structural features of the red blood cell membrane in patients with prolonged persistence of hepatitis B virus (HBV) and hepatitis C virus (HCV). MATERIALS AND METHODS: 61 patients with moderate and mild chronic viral hepatitis B and C were examined. A control group comprised 22 healthy donors. Fluorescence of the red blood cell membrane was performed, by using the following probes: pyrene, phenylnaphthylamine, 1-anilinonaphthalene-8-sulfonate. The activity of the ion-transporting enzyme Na+, K(+)-ATPase was determined. RESULTS: Increases in the microviscosity of the lipid bilayer, periprotein lipid environment, as well as the structural modification of the surface layers of the membrane were found in patients with chronic hepatitis B and C. The activity of the membrane-bound enzyme Na+, K(+)-ATPase was statistically significantly decreased as compared with that in healthy donors. CONCLUSION: In HBV and HCV infection, the impairments of the red blood system are highly diversified: they involve bone marrow compartment of an erythron, as earlier shown, and its peripheral one. Molecular disorganization of the red blood cell membrane fails to present with obvious red blood cell dysfunctions. Despite the multifactorial property of their occurrence, impairments of the red blood system are mediated and corrected by many regulatory mechanisms at different organizational levels and may be compensated.     

Antiviral preparations in the therapy of chronic viral hepatitis]

The author analyzes current data on the potentialities of antiviral therapy of patients suffering from chronic viral hepatitides. Provides the data on the short- and long-term therapeutic effects of interferon drugs and other antiviral agents, describes side effects produced by such type drugs. Compares the clinico-enzymatic, pathohistologic characteristics of the liver status with the degree of elimination of serum antigenic markers of virus B hepatitis in patients afflicted with chronic viral hepatitides. Relates the effects of antiviral drugs in patients suffering from chronic virus non-A non-B hepatitis.     

Oligoclonal immunoglobulins in serum of patients with chronic viral hepatitis

Zone electrophoresis on agarose gel was performed in serum samples from patients with chronic viral hepatitis. On the basis of the clinical, serological, and biochemical evaluation, the patients were divided into three categories: chronic type B hepatitis; chronic type delta hepatitis; and chronic non-A-non-B (NANB) hepatitis. The results of the electrophoretic analysis showed a high incidence of oligoclonal immunoglobulin bands (OIBs) in patients with chronic B hepatitis and chronic delta hepatitis and a low incidence of OIBs in patients with NANB. Since other biochemical and serological characteristics are variable and do not correlate with clinical symptoms of disease, we suggest that oligoclonal immunoglobulins could be used as a marker to aid in studies of the natural history and pathologic course of the various types of chronic hepatitis.