Article

Efficacy of vitamin E in children with immunotolerant-phase chronic hepatitis B infection

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Abstract

The purpose of the present paper was to investigate the efficacy of vitamin E in children with immunotolerant-phase chronic hepatitis B virus (CHB) infection. Fifty-eight immunotolerant children were prospectively and randomly recruited into two groups. Group 1 (study group) included 30 patients who received vitamin E at a dose of 100 mg/day throughout 3 months; group 2 (control group) contained 28 patients who did not receive any medication. Comparison of serological, virologic, and biochemical response ratios were done at the end of the therapy and after 6 months of vitamin E discontinuation. Mean alanine transaminase (ALT) values in group 1 at the beginning of the therapy, 3 months after the therapy initiation and 6 months after discontinuation were 30.4 +/- 7.3 IU/L, 31.3 +/- 7.8 IU/L and 32.1 +/- 8.5 IU/L, respectively. The mean hepatitis B virus (HBV)-DNA load of group 1 at onset, and at the third and ninth months of the treatment were 3106 +/- 718 pg/mL, 3530 +/- 137 pg/mL and 3364 +/- 1246 pg/mL, respectively. These changes in both ALT and HBV-DNA values did not reach significant levels (P > 0.05). In group 2, mean ALT values at the beginning of therapy, and at the third and ninth months were 28.0 +/- 1.8 IU/L, 34.6 +/- 8.1 IU/L, and 34.1 +/- 7.0 IU/L, respectively (P > 0.05), and mean viral load of HBV-DNA was 4227 +/- 1435 pg/mL, 3368 +/- 2673 pg/mL, and 3018 +/- 2814 pg/mL, respectively (P > 0.05). There was no statistically significant difference between group 1 and group 2 at the third and ninth months in the mean ALT values and viral load of HBV-DNA (P > 0.05). Hepatitis B s antigen and hepatitis B e antigen clearance or hepatitis B s antibody and hepatitis B e antibody seroconversion were not observed in either group. As a first study investigating the effect of vitamin E in children with immunotolerant CHB infection, no beneficial effect could be demonstrated. Different immunomodulator protocols should be considered for future investigations.

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... On the basis of the available data concerning the dosage of fat-soluble vitamins as treatment of viral infections (HBV, HCV, HIV, etc.), it may be suggested that these micronutrients should be used as drugs and not as simple dietary supplements, with the purpose to obtain proper serum and tissue concentration (78,79,103,105) . To date, the possible effective dosage of these micronutrients for the therapy of the acute infection caused by SARS-CoV-2 is unknown, as no trials have been concluded in these patients with this purpose. ...
... Therefore, it may be conceivable to take into account the dose of vitamins A, D and E in the studies performed in patients with HBV/HCV/HIV persistent infection as well as in patients with autoimmune diseases, like rheumatoid arthritis (103) . The potential doses are indicated in Fig. 5 (77)(78)(79)(105)(106)(107)(108)(109)(110)(111)(112)(113)(114) . In elderly people with moderate/severe deficiency in these micronutrients, it may be useful to consider schedules for the supplementation of all these vitamins with the purpose to reach normal tissue and serum concentrations of these fat-soluble vitamins. ...
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... In a more recent study, fifty-eight HBeAg-positive children with normal ALT levels and a high viral load received either vitamin E or no treatment (50) . Vitamin E failed to either reduce the viral load or promote HBeAg seroconversion. ...
... However, the use of vitamin E in the treatment of chronic hepatitis B provides some interesting cues. Only one study reported a complete clinical failure, but it was conducted on immunotolerant children treated with a lower vitamin E dosage than that administered in the other paediatric study (50,51) . This may suggest that 'successful' stimulation of the immune system by vitamin E could be obtained mainly in the immunoclearance phase, since the immune system is too silent and weak in immunotolerance to be reinforced. ...
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Chapter
Diet plays a fundamental role in the nutritional status, in the homeostasis and in the capacity of an individual to adapt to the environment. A proper or an inadequate nutrition has an impact on the persistence, remission and incidence of various conditions, including the infectious diseases. Consequently, nutrition has a crucial importance on survival rates and health recovery of individuals or even populations around the globe. The synergistic relationship between nutritional needs and infectious processes has been demonstrated conclusively in diverse studies. This chapter will discuss the most important nutrients, their most common natural dietary sources, the different digestive processes for each one as well as the absorption, transport, storage, excretion and function of each of the nutrients within the organism. We also go through some concepts on the interaction between nutrition and the immune system, as well as examples on the influence of nutrition or specific nutrients on some infectious diseases, and their influence on the gene expression.
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Epidemiological studies have shown that diets rich in one or more antioxidant nutrients may reduce the risk of cancers of the lung, uterine cervix, mouth, and gastrointestinal tract. Study of premalignant lesions offers a comparatively expedient approach to identifying and evaluating the efficacy of the cancer chemopreventive components of foods. Some recent findings suggest roles for beta-carotene and/or vitamin C in reversing or reducing the risk of cervical dysplasia and oral leukoplakia. There are some indications that vitamin C and beta-carotene may reduce the risk of atrophic gastritis and gastric cancer. Additional epidemiological and molecular biology studies and clinical intervention trials using premalignant lesions as the marker of specific cancer risks should become an important component of future research in the area of cancer chemoprevention.
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Twenty-one pretreatment variables were assessed for their significance in response prediction using data from 114 patients given alpha-interferon for chronic hepatitis B virus infection. In those patients who had received a minimum of 90 million units per m2 total dose over 12 weeks, a negative anti-human immunodeficiency virus antibody status (p less than 0.001), chronic active hepatitis on liver biopsy (p less than 0.005), high AST level (p less than 0.001), low hepatitis B virus DNA level (p less than 0.001) and a history of acute hepatitis (p less than 0.005) were all associated with an increased likelihood of response on univariate analysis. On stepwise logistic regression analysis, hepatitis B virus DNA, AST and a history of acute hepatitis predicted response independently (p less than 0.05). The most reliable combination of predictive factors was a negative anti-human immunodeficiency virus antibody status, with either a positive history of acute icteric hepatitis and AST greater than 45 IU per liter or no history of acute icteric hepatitis and AST greater than 85 IU per liter, which predicted response in 77% with a specificity of 79% (p less than 0.001). The loss of HBsAg in addition to HBeAg and hepatitis B virus DNA was more likely to occur in patients with chronic infection of less than 2 years duration (p less than 0.001).
Article
Vitamin E caused a generalized reduction in the metabolism and cell surface expression of glycosphingolipids (GSL) in cultured Kirsten murine sarcoma virus-transformed nonproducer (K3T3) cells. Metabolism of gangliosides was decreased two- to fourfold in cells treated for 72 hr with 1 and 2 micrograms/ml but not with 12 micrograms/ml vitamin E compared to control cultures. This was demonstrated by a quantitative reduction in precursor 3H-galactose label incorporated in ganglioside fraction and further substantiated by thin layer chromatography of colorimetrically and radiochemically detected GSL homologues. The composition of neutral GSL homologues was only slightly changed. The cell surface expressions of sialoglycoconjugates, analyzed by selective periodate-borotritide labeling, were also diminished quantitatively. These results are discussed in light of a previously demonstrated increase in antigenicity of K3T3 cells treated with vitamin E and the reduced tumorigenicity of these cells when transplanted into mice fed vitamin E-supplemented diets.
Article
The human diet contains a great variety of natural mutagens and carcinogens, as well as many natural antimutagens and anticarcinogens. Many of these mutagens and carcinogens may act through the generation of oxygen radicals. Oxygen radicals may also play a major role as endogenous initiators of degenerative processes, such as DNA damage and mutation (and promotion), that may be related to cancer, heart disease, and aging. Dietary intake of natural antioxidants could be an important aspect of the body's defense mechanism against these agents. Many antioxidants are being identified as anticarcinogens. Characterizing and optimizing such defense systems may be an important part of a strategy of minimizing cancer and other age-related diseases.
Article
The effect of vitamin E on the modulation of interleukin-2 (IL-2) dependent cellular growth, glycosylation, and expression of certain glycoproteins (GP) was examined in a murine cytotoxic T-cell line (CTLL). CTLL cultures in log phase and growing in 10% IL-2 medium in the presence of 1-16 micrograms vitamin E/ml showed a dose-dependent 2- to 15-fold stimulation of growth (assessed by 3H-thymidine incorporation) relative to controls. Vitamin E-treated cultures were observed to grow more efficiently at lower levels of IL-2 compared to controls. Glycoconjugate biosynthesis (assessed by 3H-galactose incorporation) was stimulated 5- to 15-fold by the addition of vitamin E to the culture medium. GP glycosylation as determined by wheat germ agglutinin binding GP (50-64 Kd) and concanavalin A binding GP (38-200 Kd) increased significantly in the presence of vitamin E. These results demonstrate that vitamin E stimulates IL-2 dependent cellular growth, glycosylation, and expression of certain GP in CTLL.
Article
The association between high intake of fruit and vegetables and low incidence of certain cancers is well established. Dietary antioxidants present in these foods are thought to decrease free radical attack on DNA and hence to protect against mutations that cause cancer, but this causal mechanism remains conjectural. We have adopted a molecular epidemiological approach to this question, based on a modified alkaline single-cell gel electrophoresis assay ("comet assay") which specifically detects oxidation of pyrimidines in the DNA of human lymphocytes. In a survey of men 50-59 years of age living in the northeast of Scotland, smokers initially showed significantly more base damage than nonsmokers. Correlations between oxidative base damage and plasma concentrations of various antioxidants were generally negative but not statistically significant. Supplementation of the diet for 20 weeks with vitamin C (100 mg/day), vitamin E (280 mg/day), and beta-carotene (25 mg/day) resulted in a highly significant (P < 0.002) decrease in endogenous oxidative base damage in the lymphocyte DNA of both smokers and nonsmokers. In addition, lymphocytes of antioxidant-supplemented subjects showed an increased resistance to oxidative damage when challenged in vitro with H2O2. These findings strongly support the hypothesis that fruit and vegetables exert a cancer-protective effect via a decrease in oxidative damage to DNA.
Article
RRR-alpha-Tocopherol (Vitamin E) was assayed in plasma of 48 patients with viral hepatitis and of 32 healthy controls. In patients with highly elevated serum transaminases (ALT > 100 U/L) vitamin E plasma levels were significantly lower (17.5 +/- 4.8 mumol/L) than in controls (22.7 +/- 4.2 mumol/L, p < 0.01). The vitamin E/lipid ratios (3.12 +/- 0.63 mumol/g) in these patients were 33% lower than those of the controls (4.68 +/- 0.54 mumol/g). The lowered vitamin E levels in patients with acute or chronic viral hepatitis with high activity of disease may be due to free radical-mediated liver injury.
Article
The cytokine pattern secreted by T cells at the site of viral replication may influence the final outcome of hepatitis B virus (HBV) and hepatitis C virus (HCV) infections. The aim of this study was to assess whether a cytokine imbalance oriented toward T helper (Th) 1 or Th2-type responses may play a role in chronic hepatitis B or C. Production of interferon (IFN)-gamma, interleukin (IL)-4, and IL-5 by wide series of T-cell clones derived from the liver of 6 patients with chronic hepatitis B (291 clones) and 9 patients with chronic hepatitis C (260 clones) was studied. T-cell clones were generated by limiting dilution from freshly isolated mononuclear cells derived from liver tissue to give a reliable representation of the intrahepatic inflammatory infiltrates. The majority of liver-infiltrating T cells in chronic hepatitis C were Th1 cells able to secrete IFN-gamma but unable to secrete IL-4 or IL-5, whereas in hepatitis B, most CD4+ and CD8+ liver T cells were ThO-like cells able to produce not only IFN-gamma but also IL-4 and IL-5. The different cytokine profiles of T cells within the liver in chronic HBV and HCV infections illustrate a different behavior of the local immune response in these two infections that may have pathogenetic implications.
Article
Vitamin E, the most effective natural free radical scavenger identified to date, is taking America by storm-and apparently for good reason. Reports of benefits ranging from Improved Immunity to prevention of cancer and cardiovascular disease are appearing regularly. In this article, the authors review the scientific literature to help you evaluate whether patients might benefit from supplemental vitamin E.
Article
Vaccine therapy is now used in various infectious diseases. The hepatitis B virus (HBV) leads to chronic infection in around 5% of patients with a high risk of chronic active hepatitis which may result in cirrhosis and hepatocellular carcinoma. The partial efficacy of antiviral therapies (40% of sustained inhibition of HBV replication), their cost, their possible side effects and the immune-mediated pathology of HBV infection explain the need of new immune therapies in treating HBV infection. Experimental and clinical evidences suggest the usefulness of vaccine therapy in HBV chronic infection. In a pilot and opened study, forty-six consecutive chronic HBsAg carriers with chronic hepatitis and detectable serum HBV DNA were given 3 standard injections of the GenHevac B vaccine at one month interval. Six months after the first injection, 12 patients (26.1%) had undetectable HBV DNA while 8 others showed significant decrease (more than 50%) in HBV DNA titers. Six of these 12 responders received a standard course of alpha-Interferon (5 MU thrice weekly subcutaneously for 4 months) and all six had still undetectable HBV replication at the end of follow-up. Among the 34 non responders to vaccine, 20 were given alpha-interferon and 2 the monophosphate derivate of Vidarabine: 12 of these 22 patients stopped HBV replication and in all 12, vaccine therapy had induced a significant decrease of HBV replication before the antiviral treatment with a decrease of mean serum HBV DNA from 392 pg/ml before to 217 pg/ml after vaccine therapy. In an ongoing controlled study, using the same vaccine schedule, serum HBV DNA disappeared more frequently after 6 months, in patients who were given a preS2/S vaccine (7/35) than in patients who received a S vaccine (1/21) or no vaccine (1/32). In responders to vaccine, an induction of specific proliferative responses was observed and this may contribute to the potential efficacy of anti-HBV vaccine therapy. No side-effect or vaccine-induced escape-mutants occurred during the follow-up. In summary, serum HBV DNA disappeared in 28 of the 46 patients (60.9%) who were given vaccine therapy, with (64.2%) or without (55.6%) Interferon. These results are not different at 6 months and at the end of follow-up from those of 43 HBsAg chronic carriers who were given only an antiviral treatment. Active immune therapy against HBV appears efficient and less expensive than antiviral therapies in stopping HBV replication. Such results need to be confirmed by the completed results of our controlled, randomized trial which is now conducted in our unit.
Article
Acute and chronic hepatitis B virus (HBV) infection is a leading cause of liver disease worldwide. It is estimated that approximately 350 million people worldwide have chronic HBV infection and that 1 million persons die each year from HBV-related chronic liver disease. In the past decade, significant progress in the understanding of the molecular virology and pathogenesis of HBV infection has been made. In addition, effective treatment modalities have been developed for persons with chronic infection. Worldwide, prevention of HBV transmission has become a high priority. In 1992, the Global Advisory Group to the World Health Organization recommended that all countries integrate hepatitis B vaccine into national immunization programs by 1997. Currently, 80 countries have done so and several others are planning to. Many countries have reported dramatic reductions in the prevalence of chronic HBV infection among children born since the hepatitis B vaccine was introduced into infant immunization schedules. Recent reports from Taiwan indicate a reduction in the incidence of liver cancer among children as a result of widespread hepatitis B vaccination programs.
Article
A new antiviral and immunomodulating preparation Viferon, produced as rectal suppositories containing recombinant alpha-2b-interferon (IFN) and antioxidants, was used in complex therapy of viral chronic hepatitides B and C (ChHB and ChHC) in children. Results of our investigation showed a high efficiency of Viferon. Viferon was found to suppress replication of hepatotropic viruses and to decrease activity of the pathologic process in the liver of children with ChHB and ChHC. After a Viferon treatment with daily doses of (1-2) x 10(6) IU of IFN (3.0 x 10(6) IU/m2) primary remission was registered in 78% of patients with ChHB and in 44% of patients with ChHC, while lasting remission was found in 82% of ChHB and in 33% of ChHC patients. Thus, a more marked effect was observed with ChHB, in which 3.0 x 10(6) IU/m2 was the optimal daily dose for children. Increasing the dose to 5.0 x 10(6) IU/m2 did not result in rise of the percentage of the remissions. Side effects, which are characteristic for injection of IFN preparations, were never found even after a longterm treatment. Absence of induction of neutralizing antibodies was observed after administration of alpha-2b-IFN, an integral part of Viferon. In pediatrics, the method of rectal administration has advantages over parenteral delivery due to its convenience, non-traumatic character and possibility of use for prolonged periods.
Article
Viral hepatitis B is an enigmatic disease in which the host's own immune response to persistent viral infection may bring about host destruction through antiviral inflammatory responses which might otherwise present as a benign or inapparent disease. The simple solution to the hepatitis B problem is by immunoprophylaxis using the vaccine licensed in 1981, which prevents both infection and the late sequelae of liver cirrhosis and hepatocarcinoma. Immunotherapeutic vaccines against persistent hepatitis B infection have not been successful and new explorations are being directed to therapies which include antisense, ribozymes, gene silencing by RNA interference (RNAi) and aptamer approaches. Limited benefits from nucleoside therapy and limitations in opportunity for liver transplantation have left a large void of curative treatments. Findings with respect to e antigen tolerance provide a basis for exploration to determine whether passively administered e antigen might suppress cell-mediated immunity, creating a commensal state in which virus persists but without pathologic damage to the host. Therapy of hepatocarcinoma by conventional chemotherapy, radiation, or surgical resection and ablation gives little hope for restoration of health unless the tumor is detected very early. The large engagement of the world medical science community to develop therapeutic vaccines against cancer is now in major clinical trials to determine the hope and credibility for the immunization approach. Vaccines based on tumor peptides which are linked to heat shock proteins and directed to host dendritic cells give reason for excitement and may be the "best show in town". A new era of tumor therapy will need to be based on new discoveries in immune function which are required to pursue immunotherapy on a more rational basis. The many facets of current hepatitis B virology, pathogenesis, immunoprophylaxis, immunotherapeusis, chemotherapy, and tumor pathogenesis and therapy are discussed here, in depth, but in keeping with needed brevity.
Article
Some children with chronic hepatitis B develop advanced liver disease. Lamivudine, an oral nucleoside, is a therapeutic option. A recent large, multicenter study demonstrated that lamivudine was superior to placebo in eliciting loss of hepatitis B e antigen (HBeAg) and hepatitis B virus (HBV) DNA from serum in children (2 to 17 years) treated for 52 weeks. To identify pretreatment factors that predict the likelihood of response to lamivudine in children with chronic hepatitis B infection. Data from the multicenter trial in 297 children (191 lamivudine, 96 placebo) were analyzed for the effects of baseline factors on the likelihood of responses. These responses included virologic response, defined as loss of HBeAg and HBV DNA, and HBeAg seroconversion, defined as loss of HBeAg and development of antibody to HBeAg. Univariate and multivariate analyses examined the effects of lamivudine treatment, age, gender, race, body weight, body mass index, previous interferon treatment and baseline alanine aminotransferase (ALT), histologic activity index (HAI) score and HBV DNA on the virologic responses. In the univariate analysis higher baseline ALT, higher HAI score and lower HBV DNA level predicted a greater likelihood of virologic responses to lamivudine. In the multivariate model only baseline ALT and HAI score were predictive of responses. There was no effect of age or ethnicity on response. Children with higher pretreatment ALT and HAI scores are most likely to respond to lamivudine. Age, ethnicity and other factors do not significantly influence the frequency of virologic responses in children with chronic hepatitis B infection.
Article
Despite the presence of an effective prophylactic vaccine since 1982, more than 350 million people of the world are now chronically infected with hepatitis B virus (HBV). In one scenario, a considerable numbers of chronic HBV carrier would eventually develop serious complications like liver cirrhosis and hepatocellular carcinoma. In another, chronic HBV carriers would be permanent sources of HBV infection and transmit HBV to uninfected healthy individuals. Taken together, chronic HBV infection represents a major global public health problem, especially in the developing nations of the Asia and Africa, where most of the chronic HBV-carriers reside. Unfortunately, there is no good curative therapy approach for these patients. The prospect of treatment of chronic HBV infection by antiviral agents like type-1 interferons and lamivudine is not satisfactory due to their low efficacy, considerable side effects and high costs. Vaccine therapy, an immune therapy, has recently shown considerable optimism for treating patients with chronic HBV infection. In this review, we will first describe the pathogenesis of chronic HBV carrier state to provide scientific and ethical rationales of vaccine therapy in chronic HBV carriers. Next, we will summarize the information that has been compiled from ongoing clinical trials of vaccine therapy in chronic HBV carrier. Finally, we will discuss the mechanism of action of vaccine therapy in patients with chronic HBV infection and HBV transgenic mice, a murine model of chronic HBV carrier state. This information will be valuable for developing next generation therapeutic vaccines for the management of chronic HBV infection.
Treatment of Hepatitis B
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