Southern hybridisation analysis of HBV DNA in peripheral blood leucocytes and of different cell types: changes during the natural history and with interferon-alpha therapy in patients with hepatitis B virus infection.

Hepatitis B virus (HBV) DNA was evaluated in peripheral blood mononuclear cells (PBMC) from 50 individuals utilising Southern hybridisation analysis. HBV DNA sequences were detected in PBMC from 16/29 (55 percent) of chronic hepatitis B virus (HBV) carriers with serum HBeAg and HBV DNA, compared with 1/8 (13%) of carriers with anti-HBe and HBV DNA negative (P = NS). Two of 7 patients with previous HBV infection and chronic liver disease had detectable HBV DNA in PBMC. Of the 19 patients with HBV DNA in PBMC, 18 had high molecular weight species. In addition, five of these had free, monomeric HBV DNA and six patients had low molecular weight bands. For nine of the above patients, total peripheral blood leucocytes were separated into PBMC and polymorphonuclear cells. Four had HBV DNA in PBMC only, two only in polymorphonuclear cells and three in both types of cell. Eleven patients with chronic HBV infection were studied at monthly intervals for 6 months. Six were untreated and five received IFN-alpha. Three patients who responded to IFN-alpha had HBV DNA present in PBMC before therapy, and two became negative. Two of 3 untreated patients had intermittent HBV DNA in PBMC and the other remained persistently negative. Of the patients positive on more than one occasion, the pattern of HBV DNA was similar. Peripheral blood leucocytes often contain multimers of free HBV DNA, more commonly in patients with serum HBeAg and HBV DNA and may occur even in the absence of serum HBsAg. These findings have implications for recurrence of disease after hepatic transplantation.(ABSTRACT TRUNCATED AT 250 WORDS)

Comparison of serum procollagen III peptide concentrations and PGA index for assessment of hepatic fibrosis.

In early hepatic fibrosis, increased amounts of type III collagen are deposited. Persistently high serum concentrations of aminoterminal type III procollagen propeptide (PIIIP) correlate with the activity of the fibrogenic process. Another index for the detection of fibrosis, the PGA index, combines the prothrombin time, gamma-glutamyl transpeptidase activity, and serum apolipoprotein A1 concentration (the latter falls with progressive fibrosis). We compared PIIIP measurements and PGA index in patients with various histological forms of alcoholic liver disease (104), primary biliary cirrhosis (38), and chronic B virus hepatitis (27), and in healthy age-matched controls (30). The ability of each test to identify correctly patients with fibrosis or cirrhosis was assessed with receiver operating curves. The PGA index was much higher in all groups of patients with alcoholic liver disease than in controls (p < 0.0001). PIIIP concentrations were also substantially higher than in controls (p < 0.05 for fatty liver, p < 0.0001 for all other groups), especially in the group with alcoholic hepatitis and cirrhosis. For the detection of cirrhosis the PGA was 91% sensitive and 81% specific and the PIIIP concentration was 94% sensitive and 81% specific. The two tests combined had 85% sensitivity, but 93% specificity. Among patients with primary biliary cirrhosis, both PGA index and PIIIP concentration correlated well with the severity of the disease, determined by the Mayo score (r = 0.72 and 0.66 respectively). The combined tests were 96% sensitive for the detection of fibrosis. All patients with chronic B virus hepatitis had raised PGA and PIIIP values in comparison with controls (p < 0.0001) but there were no differences between subgroups. Substantially raised PIIIP concentrations thus identify the subgroup of alcoholic patients with both hepatitis and cirrhosis. The combination of PGA index and PIIIP concentration may be useful for targeting treatment with antifibrotic drugs and to reduce the need for liver biopsy.

Interferon-alpha therapy with and without interferon-alpha priming in patients with chronic hepatitis B infection.

To determine whether a priming course of lymphoblastoid interferon-alpha (IFN-alpha) enhances the efficacy of subsequent IFN-alpha therapy in the treatment of chronic hepatitis B, a randomized trial was conducted to compare IFN-alpha priming (IFN-alpha for one month; no treatment for one month) followed by IFN-alpha therapy for three months, with IFN-alpha therapy (10 MU thrice-weekly) given for three months. Thirty-seven patients seropositive for more than six months for HBsAg, HBeAg and HBV DNA, and with histological evidence of active liver inflammation, were recruited. Eight patients (40%) treated with a priming course of IFN-alpha responded to subsequent IFN-alpha therapy for three months with loss of HBV DNA and HBe seroconversion. This compared with five patients (29%), treated only with IFN-alpha therapy for three months, who lost HBV DNA and HBeAg (but only two [12%] developed anti-HBe). IFN-alpha was well tolerated, with only three patients withdrawing from the study because of 'flu'-like symptoms or inconvenience in the early phase. The better response, although not significant, may suggest a place for a short priming course of IFN-alpha in addition to the current IFN-alpha treatment regimen.

Loss of HBsAg with interferon-alpha therapy in chronic hepatitis D virus infection.

Eleven patients with chronic hepatitis D virus (HDV) infection who had chronic active hepatitis and HDV antigen on liver biopsy were randomised in a crossover therapeutic trial of interferon-alpha 2b vs. no therapy. Nine patients had a history of intravenous drug use (drug free > 6 months before therapy), 8 had histological evidence of cirrhosis, and 7 out of 10 tested were found to be seropositive for antibody to hepatitis C virus (HCV). Six patients were randomised to receive interferon-alpha 2b therapy for 1 year, and 5 patients received no therapy for 1 year followed by the same regime of interferon-alpha 2b treatment. All patients with a history of intravenous drug use found self-injection stressful, 3 patients restarted using illicit drugs, and 2 patients with active cirrhosis developed severe thrombocytopenia during therapy and treatment was stopped in these patients. Of the 6 patients who completed at least 11 months of treatment, 4 lost serum hepatitis B surface antigen (HBsAg) with 3 developing antibody to HBsAg and one patient completing treatment. Among the 6 patients who had posttreatment liver biopsy, 5 showed an improvement in liver histology (3 of them lost serum HBsAg). These results provide further evidence that interferon-alpha is beneficial in chronic HDV infection although the psychological stress associated with the treatment, especially in patients with a previous history of intravenous drug use, is not inconceivable.

Dideoxyinosine for chronic hepatitis B infection.

Six patients positive for both human immunodeficiency virus (HIV) and hepatitis B were studied to assess the effect of dideoxyinosine (DDI) on hepatitis B virus (HBV) replication. Two patients died during the follow-up period and four had at least 8 weeks of therapy. One patient demonstrated HBV DNA suppression and became transiently negative. In the remaining five patients, there was no appreciable change in HBV DNA levels during DDI therapy. DDI was well tolerated in all patients, the only significant side effect being diarrhoea. It is concluded that DDI has no notable antiviral effect in patients with chronic HBV infection when coinfected with HIV.

Prevalence of antibodies to hepatitis C in dialysis patients and transplant recipients with possible routes of transmission.

The prevalence of hepatitis C infection and possible predisposing factors was assessed in a renal unit. Of 343 patients at our renal dialysis centre, 37 (10.8%) were anti-HCV positive by a 1st-generation assay (ELISA, Ortho/Chiron) and confirmed positive in 35 (10.2%) with a 2nd-generation test (UBI, New York). Anti-HCV positivity was significantly associated with: duration of renal replacement therapy (P < 0.0001); quantity of blood transfused (P < 0.002); duration of hospital haemodialysis (P = 0.0001); duration with a functional renal transplant (P = 0.039); and aspartate aminotransferase (P < 0.0001). Logistic regression determined the following variables to be independent risk factors: duration of renal replacement therapy with a relative risk of 34.3 for 5-9 years and 87.4 when the duration was in excess of 10 years; renal transplant for less than 1 year (relative risk of 5.0); transfusion in excess of 50 units of blood (relative risk of 11.6). Clinical assessment of anti-HCV-positive patients revealed peripheral signs of chronic liver disease in 40%, hepatomegaly in 34%, and splenomegaly in 9%. This prevalence of hepatitis C infection is similar to other European and North American centres, but contrasts with low prevalence rates reported from dialysis populations in the UK. It adds further support for routine screening of blood and possibly organ donors and implementation of further infection control measures in dialysis centres.