Biomedical subjects
A M Lever
Publications and source records attributed to A M Lever.
Retroviral RNA packaging.
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Monoclonal antibody to HBsAg for chronic hepatitis B virus infection with hypogammaglobulinaemia.
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Randomised controlled trial of lymphoblastoid interferon alfa in Europid men with chronic hepatitis B virus infection.
OBJECTIVE: To confirm the findings of pilot studies that interferon alfa is an effective treatment of Europid men with chronic hepatitis B virus infection. DESIGN: Randomised controlled trial of three months treatment with interferon alfa followed by 12 months of observation. SETTING: Outpatient clinic of a tertiary referral centre. PATIENTS: 37 Treated men (six anti-HIV positive) and 34 untreated men (nine anti-HIV positive) who met the criteria for the trial. Four controls failed to complete follow up. INTERVENTIONS: The treated group received subcutaneous injections of 5-10 MU interferon alfa/m2 daily for five days, then 10 MU/m2 thrice weekly for 11 weeks. Follow up continued at monthly intervals for 12 months. Untreated controls were monitored over the same period. MAIN OUTCOME MEASURE: Hepatitis B e antigen and hepatitis B virus DNA state after 15 months of observation. RESULTS: 12 Of the 37 treated patients cleared hepatitis B e antigen and hepatitis B virus DNA, whereas only one of 30 untreated controls seroconverted over the same period--an increased response rate of 29% (95% confidence interval 13% to 45%). The life table estimate of response at 15 months was 35% in treated patients, an increase of 32% above controls (95% confidence interval 16% to 48%). The response rates in groups by predictive pretreatment variables were 12 of 31 anti-HIV negative patients (excess response 34%; 95% confidence interval 14% to 54%), 12 of 26 with chronic active hepatitis before treatment (excess response 46%; 27% to 65%), and 12 of 21 with a pretreatment serum aspartate aminotransferase activity greater than 70 IU/l (excess response 46%; 16% to 76%). The combination of these factors predicted response with a sensitivity of 100% and a specificity of 80%. Four of the 12 responders, who had all been infected for less than two years, also lost hepatitis B surface antigen. Treatment was well tolerated. CONCLUSIONS: Interferon alfa is effective in the treatment of a proportion of Europid men with chronic hepatitis B virus infection, who might be identified before treatment. Additional strategies are required to improve the rate of response.
Defective response to interferons in cells transfected with the hepatitis B virus genome.
The interferon responsiveness of two cell lines transfected with the hepatitis B virus genome was investigated. A cosmid vector containing multiple copies of the hepatitis B virus genome was transfected into FL5-1 cells; it reduced their sensitivity to interferons as measured by inhibition of the cytopathic effect of Sindbis virus challenge. Similar vectors transfected into HeLa cells reduced their sensitivity to interferon as measured by production of beta 2-microglobulin. This resistance to interferon in hepatitis B virus-transfected cells may be a trans-acting phenomenon related to nucleotide homology between hepatitis B virus DNA and sequences regulating the interferon-induced antiviral system. Alternatively, other mechanisms involving transcription or translation products of hepatitis B virus may be responsible. Hepatitis B virus-induced cellular resistance to the action of interferon may be important in maintaining the chronic carrier state.
Effect of pregnancy plasma upon in vitro parameters of cell mediated immunity.
Pregnant women were classified according to their serological status for cytomegalovirus, herpes simplex virus or rubella virus. Lymphocytes taken from non-pregnant women were shown to be able to recognise viral antigens and the mitogen phytohaemagglutinin by the measurement of proliferative responses and by the production of gamma interferon. Proliferative responses or gamma interferon production were greatly reduced in the presence of plasma taken during the first, second or third trimester and immediately post-partum. The responses then gradually returned to normal after delivery. The availability of serial sera taken before pregnancy as well as during and after pregnancy in individual women showed that this effect was maintained even when sera had been stored frozen for more than one year. Mixing experiments were performed to vary the proportion of pregnancy serum in any particular assay but this did not prove that pregnancy sera were actively suppressive. Instead, the data suggest that pregnancy sera are deficient in some factor or factors which are required to support lymphocyte proliferation. The effect was not attributable to the physiological haemodilution of pregnancy leading to a reduced concentration of putative factors nor could transferrin levels or the iron binding capacity of this protein be implicated.
Subclasses of antibodies to hepatitis B core antigen in chronic HBV infection: changes during treatment with alpha interferons and predictors of response.
Response to interferon therapy in chronic hepatitis B virus (HBV) carriers is preceded by the appearance of IgM class anti-HBc (antibody to hepatitis B core antigen). The temporal relationship and magnitude of the IgM anti-HBc response is variable suggesting that the antibody is not directly involved in hepatocyte lysis, but is merely a marker of a changed state of immunity to the nucleocapsid proteins, induced by interferon. IgG 1, 2, 3, and 4 class anti-HBc did not change during therapy, but IgG 3 anti-HBc was significantly lower in responders than non-responders. IgG anti-HBc of all subclasses was absent in two Chinese HBV carriers. Lower than normal titres of anti-HBc (p less than 0.001) were detected in human immunodeficiency virus antibody positive (anti-HIV) HBV carriers. These data indicate the presence of altered immunity to the nucleocapsid antigens in these two types of chronic HBV carrier that are known to respond poorly to antiviral therapy.
Antenatal screening for hepatitis B is medically and economically effective in the prevention of vertical transmission: three years experience in a London hospital.
We describe our experience over a three-year period in the detection of antenatal patients with hepatitis B virus (HBV) carriage, and the successful prevention of vertical transmission in the infants of HBsAg-positive women. Nine of the 26 infants born to HBsAg-positive mothers were considered to be at high risk of infection. Eight of these nine remained HBsAg-negative after passive or passive/active immunization. The majority of infants tested had anti-HBs antibody titres above 10 i.u./l from the first month. In comparison with the cost of caring for patients with chronic hepatitis B infection and decompensated cirrhosis, non-selective testing of pregnant women for HBsAg is found to be cost effective.
Interferon production in postviral fatigue syndrome.
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Presence of a partially acid-labile alpha-interferon in bronchoalveolar lavage fluid of patients with cytomegalovirus pneumonitis is associated with a poor prognosis.
In 30 patients with pneumonitis, 16 of whom had undergone bone marrow transplantation, 13 episodes of cytomegalovirus (CMV) pneumonitis were diagnosed. In three of these, alpha-interferon, which in two cases was partially acid-labile, was detected in bronchoalveolar lavage fluid. All three of these patients died. Only two deaths occurred in ten patients without detectable levels of alpha interferon in the lavage fluid. CMV pneumonitis in immunocompromised patients appears to stimulate the local production of a partially acid-labile alpha-interferon, and its presence is associated with a poor prognosis. Gamma-interferon was not found in the lavage fluid of any patient with pneumonitis.
Treatment of the chronic hepatitis B virus carrier state.
Chronic hepatitis B is no longer untreatable. With the advent of powerful antiviral agents such as adenine arabinoside, and, more importantly, with recombinant DNA technology and advanced culture systems able to produce large quantities of interferons, the prospects for treating patients with chronic hepatitis B virus (HBV) infection have changed completely. In the U.K., carriers not infected at birth are currently being treated with an approximately 50% chance of permanently inhibiting viral replication. In some of these, viral markers appear to be completely eliminated.
Erythrocyte CR1 receptors in patients with hypogammaglobulinaemia.
Erythrocyte CR1 receptors were measured in 16 patients with primary hypogammaglobulinaemia and compared with those in 14 normal controls. There was no significant difference in the number of receptors in the two populations. One patient with hypogammaglobulinaemia had a very low number of receptors and subsequently developed red cell aplasia.
Treatment of thrombocytopenia with alfa interferon.
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Alpha-interferon therapy for non-A, non-B hepatitis transmitted by gammaglobulin replacement therapy.
Three hypogammaglobulinaemic patients with non-A, non-B hepatitis transmitted by gammaglobulin replacement therapy were treated with lymphoblastoid alpha-interferon. All showed a striking improvement in serum aminotransferases after the start of each course of treatment.
IgG antibodies in intravenous gammaglobulins.
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A review of the efficacy of adenine arabinoside and lymphoblastoid interferon in the Royal Free Hospital studies of hepatitis B virus carrier treatment: identification of factors influencing response rates.
We have reviewed the results of treating over 100 HBV carriers with adenine arabinoside, adenine arabinoside monophosphate and lymphoblastoid interferon. In the homosexual group of carriers, adenine arabinoside and its monophosphate have no value. However in this group, lymphoblastoid interferon will produce a response in over 50% of cases. This lack of effectiveness of adenine arabinoside monophosphate in this group may stem from its immunosuppressant properties. In heterosexual carriers both adenine arabinoside monophosphate and lymphoblastoid interferons are effective in approximately 50% to 60% of cases. However, the response rate is different in the various racial groups. Northern European and Mediterranean people appear to respond whereas those from the Far East do not. This may reflect the fact that there are at least two mechanisms by which the chronic carrier state may arise. In 5% to 10% of adults, a relative deficiency of alpha interferon production exists, and this defect is found in the majority of HBV carriers in Western Europe. In these, interferon acts as a replacement therapy and excellent results may be obtained if the patient is treated early in the course of the disease. It would appear that as the duration of the infection increases, the virus may integrate into interferon-reactive consensus sites and prevent the cell from responding to interferon. In patients infected at birth, transplacental anti-HBc appears to modulate the immune response and, along with immaturity of the immune system at this age, results in failure to lyse infected cells. These patients do not benefit from interferon treatment: some form of immune manipulation is required.(ABSTRACT TRUNCATED AT 250 WORDS)
Mechanisms of virally induced liver damage.
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