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Biomedical subjects

H C Thomas

Publications and source records attributed to H C Thomas.

At least 163 records · Page 9Linked to original sources
PubMed1991

Treatment of hepatitis B virus infection with interferon. Factors predicting response to interferon.

Several randomised controlled trials have been undertaken to evaluate the efficacy of alpha-interferon in the therapy of chronic hepatitis B. In patients with HBe antigen-positive disease acquired in adult life the response rates vary from 25-50%. In those infected at birth, response rates are lower. 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).

Adult↗
PubMed1991

A recombinant vaccinia virus expressing hepatitis A virus structural polypeptides: characterization and demonstration of protective immunogenicity.

A recombinant vaccinia virus containing most of the P1 region of hepatitis A virus (HAV) was constructed. Cell lysates of cultures infected with the virus contained HAV proteins detectable by radioimmunoassay. Western blot analysis revealed the presence of a single protein of Mr 60K to 62K, bearing epitopes from structural polypeptides VP4, -3 and -2, and the N terminus of VP1. The size of the protein suggests that at least some of the vaccinia virus thymidine kinase is also expressed. Inoculation of tamarin monkeys with the recombinant virus resulted in the development of a specific anti-HAV immune response which was protective against challenge with a virulent strain of HAV. Recombinant viruses expressing the above region of HAV or the proteins expressed by such viruses may be useful in the development of a vaccine suitable for use in man.

Animals↗
PubMed1991

An in situ hybridization, molecular biological and immunohistochemical study of hepatitis delta virus in woodchucks.

The presence of hepatitis delta virus genomic RNA and hepatitis delta antigen was investigated in woodchuck liver and extrahepatic tissues by in situ hybridization using synthetic radiolabeled probes, Northern-blot analysis and immunohistochemical staining for hepatitis delta antigen. Hepatitis D virus RNA and hepatitis delta antigen were detected in the nuclei of infected hepatocytes but in none of the other tissues examined. Northern-blot analysis of total cell RNA confirmed these findings and revealed a series of hepatitis D virus transcripts, including full-length genomic RNA and dimers and trimers of hepatitis D virus RNA that may represent replicative intermediates. Use of single-stranded probes showed genome-size monomers and dimers to be both of genomic and antigenomic polarity, although dimers were found to be predominantly antigenomic. These findings document the strict hepatotropism of hepatitis D virus and support the rolling-circle model of genome replication for this unique, defective RNA virus.

Animals↗
PubMed1991

Association of a precore genomic variant of hepatitis B virus with fulminant hepatitis.

A variant of hepatitis B virus has been described recently in HBsAg+ Mediterranean patients who lack HBeAg and who have an unusual and severe form of chronic hepatitis. This variant is unable to produce HBeAg because of the presence of a novel translational stop codon at the end of the precore region of the genome. By direct sequencing of DNA, generated by the polymerase chain reaction, we have evaluated the association between infection with this variant and the fulminant course of hepatitis B. Eighteen patients with fulminant hepatitis B were studied. Of the 15 cases from whose serum viral DNA could be sequenced, the variant was found in the admission sera of 8 of 9 HBeAg- patients but in none of 6 HBeAg+ patients who had fulminant hepatitis B. Patients harboring the variant progressed more rapidly into hepatic encephalopathy, but those infected with the variant strain alone had a greater likelihood of survival than those infected with the normal strain or a mixture. The mutant strain may emerge spontaneously during fulminant hepatitis as occurs in chronic hepatitis B infection during seroconversion from HBeAg to antibody. Alternately, and perhaps less commonly, patients may be infected with the variant ab initio.

Base Sequence↗
PubMed1991

Prevention and treatment of hepatitis delta virus infection.

The prevention of HDV infection can readily be achieved by immunisation with the envelope proteins (HBsAg/pre-S) of the helper virus (HBV) on which HDV is dependent. In patients with established chronic HBV infection, superinfection with HDV may theoretically be controlled, but not prevented, by immunisation to the internal components of HDV which may be the target of a cytotoxic T-cell response to HDV infected hepatocytes. Such a response, by analogy to the effects of immunisation to HBcAg, may result in rapid lysis of infected hepatocytes thereby limiting the spread of HDV through the liver. In our preliminary experiments using recombinant HDAg (amino-acids 13-76) we have shown that a humoral immune response to HDV prior to HDV superinfection, does not control HDV infection but may facilitate it. We do not know whether this immunisation protocol successfully induced a cytotoxic T-cell response or whether the region of HDAg included is recognised by cytotoxic T-cells and involved in the immune destruction of HDV infected cells. Further studies of the mechanisms of lysis of HDV infected hepatocytes to determine the role, if any, of cytotoxic T-cells or humoral lytic mechanisms, is needed. Although short courses of alpha interferon inhibit HDV replication, relapses are common and amelioration of the inflammatory liver disease is not always seen. Longer periods of therapy may be effective if they can be continued until clearance of the helper virus (HBV), as well as HDV, has occurred. In three patients treated for greater than one year, clearance of HBsAg has occurred. If these patients remain in this state after stopping therapy, further studies of long term alpha interferon therapy may be fruitful.

Animals↗
PubMed1990

Vaccine-induced escape mutant of hepatitis B virus.

In southern Italy, 44 contacts of hepatitis B virus carriers, including infants of carrier mothers, became HBsAg positive despite passive and active immunisation according to standard protocols. In 32 of these vaccinees infection was confirmed by the presence of additional markers of viral replication. In 1 infant, serious disease occurred. The virus from this patient is an escape mutant with a different sequence from that of the isolate from the mother. A point mutation from guanosine to adenosine at nucleotide position 587 resulted in an aminoacid substitution from glycine to arginine in the highly antigenic a determinant of HBsAg. This mutation is stable: it is present in an isolate from the child 5 years later. In some of these patients, including this child, the a determinant, to which a large part of the vaccine-induced immunity is directed, has been partly lost. Binding to HBsAg of a monoclonal antibody, previously mapped to the region of the mutation, was reduced in the child relative to that of the mother.

Biomarkers↗
PubMed1990

Immunological studies before and during interferon therapy in chronic HBV infection: identification of factors predicting response.

Lymphoblastoid interferon is effective therapy in some but not all patients with chronic hepatitis B virus infection. To assess whether immunological parameters were predictive of response to interferon therapy, we determined the human leukocyte antigen type, CD4/CD8 ratio, natural killer cell activity, IgM anti-HBc antibody levels and concanavalin A-induced lymphocyte proliferative response in 30 patients before treatment. In addition, to investigate the mechanisms of action of interferon in promoting hepatitis B virus clearance, we serially measured the CD4/CD8 ratios, natural killer activity and lymphocyte proliferative response at wk 4, 8 and 12 of treatment. A beneficial response to therapy was defined as the sustained clearance of HBeAg and serum hepatitis B virus DNA within 1 yr of commencing therapy. Elevated IgM anti-HBc levels were associated with a beneficial response to therapy, but there was no correlation observed between response and pretreatment CD4/CD8 ratio, natural killer activity or lymphocyte proliferative response. Six of seven human leukocyte antigen DR3-positive patients responded. No measurable changes in the immunological parameters studied were observed in the nonresponder group, whereas a significant rise in CD4/CD8 ratio, associated with a fall in peripheral CD8 number and a decline in measurable NK activity, was seen in the responder group. These changes were maximal at the time of hepatitis B virus DNA clearance, which was associated with a transient increase in hepatic inflammation.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1990

Immunization of woodchucks with recombinant hepatitis delta antigen does not protect against hepatitis delta virus infection.

To assess the role of immunization against hepatitis delta antigen in the prevention of hepatitis delta virus infection, woodchuck carriers of woodchuck hepatitis virus were immunized with a 64 amino acid portion of hepatitis delta antigen from its N-terminal region. The protein was expressed in Escherichia coli and contained a major immunogenic epitope. A significant anti-hepatitis delta response was observed that did not, however, protect the animals from hepatitis delta virus superinfection. Unexpectedly, the period of detectable viremia was longer in the immunized than in the control animals. We conclude that immunization with this recombinant hepatitis delta antigen does not afford protection against subsequent hepatitis delta virus exposure.

Animals↗
PubMed1990

Protracted alanine aminotransferase levels in tamarins infected with hepatitis A virus.

Eighteen red-bellied tamarins (Saguinus labiatus), experimentally infected with hepatitis A virus (HAV), were followed for up to 1.5 years after initial challenge. Half of these animals developed protracted alanine aminotransferase (ALT) abnormalities, which lasted for between 23 and 55 weeks post-challenge. IgM anti-HAV was detected intermittently during the early phase of their relapsing hepatitis and never after return of ALT levels to normal. The possibility that these findings may be related to continued HAV replication, coinfection with another agent, or the result of an autoimmune phenomenon triggered by HAV are discussed.

Alanine Transaminase↗
PubMed1990

Anti-HBs response in seroconverting chronic HBV carriers following alpha-interferon treatment.

The antibody response to hepatitis B surface antigen (anti-HBs) was studied in 15 chronic hepatitis B virus (HBV)-infected patients who seroconverted following treatment with alpha interferon. The levels of anti-HBs (IU/l) attained were significantly lower than those recorded in patients with convalescent symptomatic or asymptomatic acute infection and in hospital personnel who received a plasma derived HBV vaccine.

Adolescent↗
PubMed1990

The hepatitis B virus and the host response.

The clearance of hepatitis B virus infected cells from the liver is probably dependent on an interplay between the interferon system and the cellular limb of the host immune response. Although the importance of the nucleocapsid proteins as targets for sensitized cytotoxic T cells is established in chronic hepatitis B infection, further studies are needed during the early phase of acute infection. The relative importance of pre-S sequences as inducers and targets of the virus neutralizing humoral immune response is becoming established but their precise place will await the development of in vitro models of hepadna virus infection and precise definition of the mechanism of viral uptake. In adult life, deficient production of alpha-interferon and suppression of the ability of the host to respond to interferon are probably important factors underlying the development of chronic infection. In the neonate, however, specific suppression of the cell-mediated immune response may be involved. The presence of a mutation in the pre-core region of some virus isolates has recently been described. Hepatocytes infected with this virus cannot produce hepatitis B e antigen and the course of the liver disease is fairly rapid. Whether this mutant causes liver damage in the same way as the wild virus or is directly cytopathic needs further study. In adult-acquired chronic hepatitis B virus infection, alpha-interferon produces hepatitis B e antigen clearance in 26-88% of cases and is followed by resolution of the hepatic inflammation. Results in neonatally acquired infection are less impressive and prednisolone priming followed by interferon may be needed.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1990

The hepatitis B virus.

Of all the hepatotropic viruses, HBV is associated with the greatest worldwide morbidity and mortality. This is because of the ease of transmission and the potential for progression to a chronic infective carrier state, with the complications of cirrhosis and hepatocellular carcinoma. The use of PCR has shown that some of the earlier concepts concerning the interpretation of serological data were inaccurate. Many patients with anti-HBe and anti-HBs have viral DNA detectable by PCR, and some hepatocellular carcinoma patients have detectable HBV DNA in their livers in the absence of all serological markers of HBV disease. The clearance of HBV infected cells from the liver is dependent on the interplay between the interferon system and the cellular limb of the host immune response. The importance of the nucleocapsid proteins as targets for sensitized cytotoxic T cells has been established for chronic HBV infection. The importance of pre-S sequences as inducers and targets of the virus-neutralizing humoral immune response is becoming established, but their precise role must await the development of in vitro models of hepadnavirus infection and a greater understanding of the mechanisms of viral uptake. The epidemiology and clinical course of the disease can be modified by immunization, immune stimulation and antiviral chemotherapy. For the developing world, a programme of immunization at birth would be the most effective way of eliminating this disease, but at present the cost is prohibitive. For the developed world, immunization is realistic for the at-risk population, and anti-viral and immunostimulatory therapy available for those already infected. In adult acquired chronic HBV infection alpha-interferon produces HBe antigen clearance in 40-60% of cases and is followed by resolution of the hepatic inflammation. Results in neonatally acquired infection are less impressive and prednisolone priming followed by interferon may be needed. The presence of a mutation in the pre-core region of some virus isolates has recently been described. Hepatocytes infected with this virus cannot produce HBe antigen and the course of the liver disease is fairly rapid. Whether this mutant causes liver damage in the same way as the wild virus or is directly cytopathic remains unclear, and its relationship to fulminant hepatitis is under investigation.

Adolescent↗