Giorgio Verme

INFLUENCE OF DELTA INFECTION ON SEVERITY OF HEPATITIS B

The prevalence of serum markers of primary delta infection was determined in 532 patients with acute benign hepatitis B seen in Italy, and in 111 patients with fulminant hepatitis B seen in Italy, France and England. Patients with fulminant hepatitis had significantly higher prevalence of delta markers (43/111, 39%) than did those with benign hepatitis (101/532, 19%). In 25 of the 43 patients with delta-positive fulminant hepatitis, serum markers indicated a primary hepatitis B infection while in the remaining 18, IgM antibody to hepatitis B core antigen was absent, indicating that hepatitis B preceded superinfection with the delta agent. The increased morbidity of HBsAg hepatitis with delta infection may result from the cumulative simultaneous exposure to hepatitis B virus and delta, or from superinfection of HBsAg carriers with delta.

Chronic Hepatitis in Carriers of Hepatitis B Surface Antigen, with Intrahepatic Expression of the Delta Antigen: An Active and Progressive Disease Unresponsive to Immunosuppressive Treatment

To assess the characteristics of chronic hepatitis in hepatitis B surface antigen (HBsAg) carriers with intrahepatic delta antigen, the hepatic histologic findings of 137 patients were reviewed; 101 patients were followed for 2 to 6 years. The predominant liver disease was chronic active hepatitis in 93 patients or cirrhosis in 32; minor forms of chronic persistent or lobular hepatitis were seen in 12 patients. Eight of the 26 patients with an initial diagnosis of cirrhosis died during the follow-up period. Cirrhosis developed in 31 of 75 patients (41%) without nodular regeneration seen in the first biopsy specimen; 5 of these patients died. Treatment with prednisone or azathioprine did not induce histologic amelioration of delta hepatitis or prevent cirrhosis. Chronic HBsAg hepatitis with intrahepatic expression of the delta antigen is an active, progressive disease unresponsive to conventional immunosuppressive treatment.

Hepatitis B virus unable to secrete e antigen and response to interferon in chronic hepatitis B

BACKGROUND Anti-hepatitis e antigen-positive chronic hepatitis B is a progressive liver disease associated with precore mutant hepatitis B virus (HBV) and poor response to interferon. Therefore, precore mutant HBV may behave as an interferon-resistant virus. The relations between the prevalences of wild-type and precore mutant HBVs in baseline viremias and response to interferon were analyzed. METHODS Sera from 115 patients (59 treated and 56 untreated, followed up for 30 months) were tested using a quantitative oligonucleotide hybridization assay. RESULTS Spontaneous or interferon-induced recoveries were observed in 28.5% (6 of 21) and 47.3% (18 of 38) or in 0% (0 of 35) and 19% (4 of 21) of the patients with wild-type prevalent or mutant prevalent HBVs, respectively. Relapses occurred in 85.7% (12 of 14) and 19.4% (4 of 21) of treated patients with prevalent precore mutant and prevalent wild-type HBV, respectively (P = 0.0001). High precore mutant HBV levels (> 20% of total viremia) were associated with the lack of permanent response to interferon (P = 0.01). CONCLUSIONS Precore mutant HBV can influence the response to interferon when it reaches significant serum levels (> 20% of total viremia). Therefore, chronic hepatitis B should be treated as early as possible in its natural history before precore mutant HBV is selected as a prevalent virus.

INCIDENCE AND SIGNIFICANCE OF ANTIBODIES TO DELTA ANTIGEN IN HEPATITIS B VIRUS INFECTION

A microtitre solid-phase blocking radioimmunoassay (RIA) for antibody to the hepatitis B virus (HBV)-associated delta antigen was specific and detected anti-delta antibody at dilutions of serum of up to 10(6). Analysis of sera from HBsAg-negative subjects and different categories of HBsAg carriers from different regions confirmed the association of anti-delta antibody with HBV infection. Anti-delta antibody was detected in persistently high titres in 19.1% and 2.6% of sera from patients with chronic hepatitis and symptomatic chronic carriers, respectively, and was not detected in the sera of HBsAg-negative controls. Anti-delta antibody appeared transiently and in low titres (less than 1:500) in 4.8% of sera from patients with acute type B hepatitis. The presence and persistence of anti-delta antibody seem to be associated with chronic HBV infection and the development of progressive liver damage.

Delta hepatitis — Present status

The hepatitis delta virus (Delta) is a defective RNA pathogen dependent for replication on obligatory helper functions provided by the hepatitis B virus (HBV). The virion is a particle of 35-37 nm, which encloses within a HBsAg coat the RNA genome and the Delta antigen, the specific immunologic expression of the new pathogen. Infection is diagnosed by the presence of Delta antigen in liver and the finding of antibody to Delta in serum. The virus is infectious for primates but can also adapt to non-primates. Distribution is world-wide with peak prevalence in the Mediterranean basin, the Middle East and areas of Africa. Transmission occurs by direct parenteral inoculation and by non-parenteral routes linked to close body contacts. Delta is highly pathogenic and a cause or an aggravating factor of HBsAg-positive liver disease. Infection superimposed on acute HBV hepatitis may induce a fulminant illness. Superinfection of carriers of HBsAg may convert a previously asymptomatic carrier in a carrier with chronic hepatitis, or accelerate the downward clinical course of chronic underlying HBV disease. Carriers of HBsAg probably represent the reservoir of the virus.

Continuously infused cyclosporine at low dose is sufficient to avoid emergency colectomy in acute attacks of ulcerative colitis without the need for high-dose steroids.

A dosage of 4 mg/kg/day intravenous cyclosporine as an adjunct to high-dosage hydrocortisone has been recommended to avoid colectomy in acute steroid-resistant ulcerative colitis. In treating eight such patients, four of whom presented with toxic megacolon, we immediately tapered the steroid dosage and infused a lower dosage of only 2 mg/kg cyclosporine for 15 days to fit a therapeutic range of 60–240 ng/ml, as previously designed for a kidney transplant program. Seven of the eight (87.5%), including three with megacolon, went into remission and started the chronic phase of treatment; the eighth patient underwent colectomy. Of the seven, one died on day 3 of the chronic phase because of pulmonary embolism while in clinical remission, and another discontinued treatment. The other five (62.5%) remain in remission on 6 mg/kg oral cyclosporine, or have already switched from cyclosporine to azathioprine. Two episodes of reversible nephrotoxicity appeared in the chronic phase only. These results emphasize the efficacy and safety of cyclosporine in acute ulcerative colitis, but there is still a need for further dose-response and drug association relationship studies.

Role of hepatitis delta virus infection in hepatocellular carcinoma

Hepatitis B virus (HBV) DNA integrates into the host DNA and shows a series of potentially oncogenetic properties, but HBV is not an acutely transforming virus, because HCC develops decades after infection. Other factors, namely cirrhosis, inflammation, alcohol intake, and viral superinfections, could promote the oncogenetic process induced by HBV-DNA integration. We studied the impact of HDV infection in the pathogenesis of HCC in 62 consecutive patients. Their mean age was 59 years (range 25–75 years), 54 were male and eight female; 58 had cirrhosis. The findings suggest that HBsAg-positive patients with HDV superinfection developed cirrhosis and HCC at an earlier age than HBsAg carriers without HDV infection. HDV appears to represent a “promotion” factor for HCC in subjects with an oncogenic risk induced by HBV. A long-lasting necroinflammatory lesion of the liver substained by productive HBV and HDV infections may be a major pathogenetic mechanism.

Chronic HDV (hepatitis delta virus) hepatitis: Intrahepatic expression of delta antigen, histologic activity and outcome of liver disease

The expression of intrahepatic delta antigen (HDAg) was studied in relation to the morphologic features of HDV hepatitis and the outcome of liver disease. The study was performed in 101 patients followed up for an average of 12 years; one or more liver biopsies were available from each patient, giving a total of 167 specimens. The histologic features were assessed using numerical scores. A significant positive relation was observed between the number of HDAg-positive cells and the extent of portal inflammation (Spearmans rank coefficient 0.75). The highest degree of inflammation and intrahepatic expression of HDAg was found before the elimination of the virus, while the outcome of HDV disease was unrelated to the severity of the initial morphologic lesion. These results suggest that the individual immune response may play an important role in the pathogenesis of HDV hepatitis.

The epidemiology of hepatitis delta infection in Italy

Abstract The epidemiology of HDV infection in Italy was assessed in a retrospective study involving 1556 HBsAg chronic carriers on their first presentation at one of the 35 Liver Units in 1987. Total anti-HD was detected in 23.4% of HBsAg carriers and was significantly more frequent in southern than in northern Italy (26.6% vs. 19.1%, p p p

Prolonged treatment (2 years) with different doses (3 versus 6 MU) of interferon α-2b for chronic hepatitis type C: Results of a multicenter randomized trial

BACKGROUND/AIMS To examine the effect of prolonged treatment with different doses of interferon alpha-2b on the relapse rate in patients with chronic hepatitis C. METHODS One hundred and seventy-one patients with non-cirrhotic chronic hepatitis C were enrolled in an Italian multicenter trial. All patients were treated for 3 months with 3,000,000 Units (3 MU) of interferon alpha-2b given subcutaneously three times a week (t.i.w.). Patients with abnormal alanine aminotransferase (ALT) values were given 6 MU of interferon for an additional 3 months. If ALT remained persistently abnormal, therapy was then suspended. If ALT levels were normal, therapy was continued (6 MU t.i.w.) for an additional 18 months (total=2 years). Patients with normal ALT were randomly assigned to two groups, one receiving 3 MU and the other receiving 6 MU t.i.w. for an additional 21 months (total=2 years). Follow-up continued for 2 years after therapy withdrawal. RESULTS Seven patients stopped treatment during the first 3 months. Of the remaining 164 patients, 76 (46%) showed abnormal ALT levels after 3 months of therapy: 11 of these (14%) normalized ALT values when given 6 MU and a sustained response was maintained in eight during the follow-up. Overall, 54 and 34 patients were allocated respectively to the groups receiving the 3 MU and 6 MU long-term treatment. At the end of therapy, 35/54 patients of the group 3 MU and 21/34 patients of the group 6 MU showed normal ALT levels (65% vs 62%, p=N.S.). After 2 years of follow-up, 24/35 (69%) patients of the group 3 MU and 16/21 (76%) of the group 6 MU were still in remission (p=N.S.). In an intention-to-treat analysis, 48/171 (28%) patients showed a long-term response (normal ALT values, HCV-RNA negative). About 65% of the sustained responders showed low baseline viremia compared with 33% of non-responders (p=0.005) while genotype 1b was more frequently found among non-responders than in long-term responders (84% vs 25%, p=0.0001). CONCLUSIONS About 14% of patients who do not respond to a 3-month course of 3 MU of interferon normalize ALT levels when given 6 MU. In prolonged treatment, there is no significant difference between 3 and 6 MU in inducing a sustained response. Patients with low baseline viremia and genotype 2a respond significantly better to prolonged interferon therapy than highly viremic patients with genotype 1b.