Treatment of chronic hepatitis B infection.
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Biomedical subjects
Publications and source records attributed to J Main.
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1. Although ethanol appears to alter cellular sodium transport, the exact nature of its effects has not been clearly defined. We have studied the effects of different concentrations of ethanol on human leucocyte sodium content, and on the rise in leucocyte sodium content which occurs during sodium pump blockade with ouabain. 2. Sodium content was significantly reduced after a 20 min incubation with ethanol at concentrations between 17 and 170 mmol/l. 3. The rise in sodium content during a 20 min incubation with ouabain was significantly less in the presence of 170 mmol/l ethanol as compared with 17 mmol/l ethanol. 4. These results suggest that the effect of ethanol on intracellular sodium content is independent of sodium pump activity, i.e. it is mediated through reduced sodium influx.
Leukocyte cation content and sodium pump transport were measured in 14 undialysed uraemic and 15 CAPD patients and compared with results from healthy controls. Sodium content was elevated in the undialysed group compared with the CAPD group (P = 0.05) or the healthy controls (P less than 0.001), but this abnormality could not be clearly attributed to increased sodium influx or reduced sodium pumping. Sodium content correlated with plasma urea (rs = 0.69, P = 0.005) and creatinine (rs = 0.56, P = 0.031) concentrations in the CAPD group only. In subgroups of 12 undialysed and ten CAPD patients, erythrocyte sodium content and pump transport were measured at the same time as the leukocyte studies. Erythrocyte sodium was less in the undialysed group (P less than 0.01) and again there was no evidence of significant sodium-pump inhibition. The abnormalities in sodium content in undialysed patients were therefore in opposite directions in the two cell types, and were significantly less in both cell types in CAPD patients. These results emphasise the dangers of assuming that abnormalities of sodium transport seen in a single cell type can be taken as evidence of a generalised abnormality.
IgG serum antibody was measured by ELISA in patients with Crohn's disease (15), ulcerative colitis (15), and in normal controls (15) to 12 strains of Saccharomyces cerevisiae (baker's and brewer's yeast) and to the two major serotypes of the commensal yeast Candida albicans. Antibody to 11 of the 12 strains of S cerevisiae was raised in patients with Crohn's disease but not in patients with ulcerative colitis when compared with controls (p less than 0.001). The pattern of antibody response to these 11 strains was variable, however, suggesting the likelihood of antigenic heterogeneity within the species. Antibody to C albicans was not significantly different in patient and control groups. The specificity of this unusual antibody response in Crohn's disease for S cerevisiae suggests that it is not simply the result of a generalised increase in intestinal permeability. Furthermore, because brewing and baking strains detected the response, the relevant antigen(s) are presumably common in the diet. Hypersensitivity to dietary antigens may be involved in the pathogenesis of Crohn's disease, and the role of S cerevisiae requires further investigation.
Because the risk factors for human immunodeficiency virus (HIV) infection and hepatitis B (HBV) are similar and therefore coinfection is not uncommon, a detailed histological and immunohistochemical study of chronic hepatitis B infection in a group of 20 HIV positive Caucasian males (who did not have AIDS) and 30 HIV negative controls were undertaken. Using both the conventional histological classification and the Knodell histological activity index it was shown that HIV negative patients were more likely to have active disease and also more scarring than HIV positive patients. Hepatitis B surface antigen (HBsAg) expression was not significantly different between the two groups but expression of hepatitis Be antigen (HBeAg) and HBV-DNA polymerase was greater in those who were HIV positive. HIV positive patients are therefore more likely to have immunohistochemical markers of active viral replication, although histologically, liver disease is less severe. These findings have important implications for assessing the biopsy specimens in this group of patients and for treatment strategies aimed at improving their immune function.
Data from 121 consecutive patients with hypertension and renovascular disease, first diagnosed between 1975 and 1982 in Glasgow and Newcastle, were analysed retrospectively to determine the factors which influenced their outcome. Thirty-six patients died between the data of arteriography and 1st January 1987, giving five and ten year survival rates of 83% and 67%. Survival was greatly reduced in comparison with that of age-sex-matched controls in the general population of the West of Scotland, and was also less than that of essential hypertensives matched for age, sex, initial diastolic blood pressure and smoking habit who had attended the Glasgow Blood Pressure Clinic during the same period. Multivariate analysis showed that age, cigarette smoking and presence of atheromatous disease were significantly and independently related to outcome among the patients with renovascular disease, whereas male sex, centre of origin, severity of hypertension when first seen, initial renal function and presence of bilateral disease were not. Despite a trend towards benefit from surgical intervention (ten year survival in medical group 62%, in surgical group 71%; p = 0.19) our data do not prove that intervention is better than medical treatment, largely because the decision on intervention was not randomised. A prospective trial would be required to answer this important question.
A 41 year old man with severe hypertension due to a renin-secreting retroperitoneal leiomyosarcoma is described. Clinical, immunohistochemical, electron microsopic and autopsy findings are presented. The origin of juxtaglomerular cells from vascular smooth muscle is briefly discussed.
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.
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OBJECTIVE: To determine the effect of low dose interferon alfa (human lymphoblastoid interferon) on aminotransferase activities in chronic non-A non-B hepatitis. DESIGN: Prospective randomised controlled parallel group study of active treatment versus no treatment carried out over 16 weeks and preceded by baseline measurements at weeks 8 and 4 and time zero. SETTING: HEPATOLOGY outpatient clinics in secondary referral centres. PATIENTS: Fourteen adults with histologically proved chronic hepatitis and persistently raised aminotransferase activities for six months or more. INTERVENTIONS: Seven patients randomised to receive interferon alfa 5 megaunits (MU) daily for one week, reducing to 5 MU thrice weekly for seven weeks, then 3 MU thrice weekly for eight weeks. Controls not treated. END POINT: Control of hepatic enzyme activity in chronic non-A non-B hepatitis. MEASUREMENTS AND MAIN RESULTS: Serum aspartate aminotransferase activity remained raised in controls (mean increase in study period 23.4 U/l) but fell rapidly to normal in the treated group (mean decrease 106.4 U/l). In four cases values were normal by eight weeks and in five cases by 16 weeks. Only minor side effects were recorded (fever, myalgia), which became less common as treatment progressed. CONCLUSIONS: Continuous low dose interferon alfa reduces aspartate aminotransferase activity to normal in most patients with chronic non-A non-B hepatitis and may prevent progression to cirrhosis.
1. Previous published measurements of leucocyte cation content are inconsistent, with sodium concentrations having particularly high coefficients of variation. We have measured the effects of recovery time after isolation, different types of handling, and centrifugation on leucocyte sodium and potassium content. 2. Sodium content fell markedly during the first 30 min after isolation and was stable from 1 to 3 h of incubation. There was a small but significant rise in potassium content over the same time period. 3. During incubation, occasional gentle resuspension of the cells gave optimal sodium contents, whereas mixing by inversion caused large falls in sodium and potassium content. 4. Centrifugation of stable cells at 200 g for 6 min caused marked increases in sodium content.
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The clearance of HBV-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 HBV infection, further studies are needed during the early phase of acute HBV 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 hepadnavirus infection and precise definition of the mechanism of viral uptake. Our understanding of the mechanisms underlying the development of chronic HBV infection is still incomplete. When this occurs in adult life, deficient production of alpha interferon and suppression of the ability of the host to respond to interferon are probably important factors, and the role of suppression of the humoral response remains to be determined. In the neonate, specific suppression of the cell-mediated immune response, perhaps because of exposure to soluble HBe antigen or to modulating quantities of maternally derived antinucleocapsid antibodies at a time when the immune system is "immature," may be involved. In each of these postulated mechanisms the virus has neutralized one important host defense. Increasing the response rate to therapy with interferon or synthetic antiviral compounds will depend on identifying the cause in each patient and devising specific therapies to reverse the host-virus balance in favor of the host defenses.