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We examined nine chronic healthy hepatitis B surface antigen/antibody to hepatitis Be carriers with consistently normal liver chemistries and negative serum hepatitis B virus-DNA. Liver biopsy, performed twice, 10-11 years apart in all patients, showed normal histology and negative hepatitis B core antigen. DNA extracted from the second liver biopsy specimen, from 1 ml of serum from each patient and from an additional serum sample of 6 ml from two patients, was tested for pre-C/C and pre-S regions of hepatitis B virus-DNA by polymerase chain reaction amplification. Viral sequences were found in six of nine liver DNA extracts. In four cases both pre-C/C and pre-S regions were amplified, while the pre-C/C alone and the pre-S alone were detected in one case each. Direct sequencing of the amplified DNAs revealed no significant genomic changes in the pre-S and Core regions, while analysis of the pre-Core demonstrated the presence of a double viral population (wild-type and "e-defective") in four cases, and only "e-defective" hepatitis B virus in one case. No hepatitis B virus genomes were revealed in the serum sample when DNA was extracted from 1 ml of serum, while viral sequences were detected in both extracts of 6 ml of serum, indicating the presence of very low levels of viremia. These data suggest that episomal hepatitis B virus-DNA may persist for years in the liver of chronic healthy carriers in a latent state which may involve both wild-type and HBeAg-defective hepatitis B virus.

A modified method for the direct sequencing of double-stranded DNA products of PCR amplification is described and has been applied to the analysis of hepatitis B virus (HBV) preC/C region in samples from persistently infected patients with chronic hepatitis. Data was obtained from both hepatitis B e antigen (HBeAg)-positive and -negative chronic carriers. A high prevalence of mixed viral populations (wild-type genomes and mutated sequences with a TAG stop codon in the distal preC region at position 1895-1897) was shown in the HBeAg-positive group; a homogeneous (either mutated or wild-type) viral population was detected in all but one of the long-term HBeAg-negative, untreated chronic carriers, thus suggesting that pre-core mutants can be rapidly generated and selected during the natural course of HBV infection.

Objective: To assess the long-term outcome in hepatitis B surface antigen (HBsAg) carriers who have normal liver function tests, focusing on survival and the development of severe liver disease and hepatocellular carcinoma., Design: Cohort study with a mean follow-up of 130 months., Setting: Liver clinic of a referral center., Patients: Ninety-two HBsAg-positive blood donors with normal liver function tests., Measurements: Histologic evaluation of liver specimens at baseline; clinical, biochemical, and serologic follow-up; and repeat liver biopsy if clinically indicated or after 10 years of follow-up., Results: At baseline, 69 subjects had normal histologic findings or only minor abnormalities, 18 had chronic persistent hepatitis, and 5 had mild chronic active hepatitis. Serum enzyme levels remained normal in 58 of 68 patients who had regular follow-up. Three patients had biochemical changes consistent with hepatitis B virus (HBV) infection; in one of these patients, a later histologic evaluation showed progression to chronic active hepatitis. One patient developed alcoholic cirrhosis. Six other patients had mild or transient transaminase elevations, with no evidence of HBV replication, hepatitis D virus infection, hepatitis C virus (HCV) infection, or histologic deterioration. Liver histologic findings also remained unchanged in 21 patients who showed no biochemical changes during 10 years of follow-up and consented to have repeated liver biopsy. Ten patients showed loss of HBsAg; 2 of these patients acquired antibody to hepatitis B surface antigen (anti-HBs). All patients who did not have regular follow-up, except 1, were interviewed by telephone during 1990: All denied having liver disease. No patients developed hepatocellular carcinoma., Conclusions: Italian HBsAg carriers with initially normal liver function tests have an excellent prognosis: Delta superinfection is infrequent and the risk for developing hepatocellular carcinoma is low.

The recognition of replicating hepatitis B virus (HBV) may be important to both define the cause of and know how to manage chronic liver disease in multitransfused hemophilic patients. Replicating HBV can be detected at the molecular level by methods for HBV-specific DNA (HBV-DNA), which are much more sensitive than the immunologic methods for detecting hepatitis B surface antigen (HBsAg) and hepatitis B e antigen (HBeAg). Unselected hemophilic patients (260; 6% with HBsAg, 4% with isolated anti-hepatitis B core (anti-HBc), 52% with anti-HBs and anti-HBc, 26% with isolated anti-HBs, and 12% with no HBV marker) were investigated retrospectively with a dot spot hybridization technique that detects serum HBV-DNA down to 0.5 pg and by Southern blot analysis, which tests the specificity of the HBV-DNA reactions. Eighteen patients (7%; five with serum HBsAg and 13 HBsAg seronegative with antibodies to HBV) had serum HBV-DNA. Serum HBV-DNA was detected more frequently in HBsAg carriers than in seronegative patients (33% versus 6%, P less than .01), and had no relationship to serum alanine aminotransferase. Serum HBV-DNA was more sensitive than the radioimmunoassay for HBeAg was for detecting replicating HBV (7% versus 1.1%, P less than .01). These findings demonstrate that there is cryptic HBV infection in a number of hemophiliacs and that serum HBV-DNA may coexist with markers thought to reflect immunity against HBV.

To assess the prevalence and clinical significance of delta-infection in chronic hepatitis B surface antigen carriers, we examined 326 liver biopsies from 192 retrospectively selected carriers by immunofluorescence. Delta antigen was detected in 102 specimens from 50 carriers (26.2%) with peak prevalence in patients with active cirrhosis (51.5%) and generally in close association with progressive liver disease (94%). The antigen was located in the nuclei of 2%-50% of the hepatocytes, without any disease-specific pattern of fluorescence. Patients with intrahepatic delta-antigen, however, had more severe liver disease than those without it. Histologic follow-up of 101 cases showed that the rates of worsening of the liver disease were similar in delta-antigen-positive and in delta-antigen-negative patients. It is concluded that delta-superinfection does play a role in worsening the histologic picture of hepatitis B surface antigen-positive chronic active hepatitis, possibly by liver injury induced acutely at the moment of infection.

The A, B, C and DR locus specificities of the human leukocyte antigens system (HLA) were determined in 45 delta-positive and 44 delta-negative Italian patients, all with HBsAg-positive chronic active liver disease; controls were 526 healthy Italian blood donors matched for age, sex and geographical origin. HLA-A, B, C gene frequencies were not significantly changed. In delta-positive patients, the frequencies of the DR locus specificities were: DR2, 37.8%; DR3, 20%; DR4, 11.1%. In the delta-negative patients, the frequencies were: DR2, 13.6%; DR3, 36.4%; DR4, 0%. Control frequencies were: DR2, 19.4%; DR3, 17.1%; DR4, 18.5%. The corrected p values of the differences between controls and delta-positive patients were: DR2, pc = 0.046; DR3, pc = NS (not significant); DR4, pc = NS. The corrected p values of the differences between controls and delta-negative patients were: DR2, pc = NS; DR3, pc = 0.03; DR4, pc = 0.002. These findings show that: (a) DR3, a genetic marker of autoimmunity, might assist the establishment of chronic HBsAg liver disease in the absence of delta superinfection; (b) DR2 is linked with failure to clear the delta agent, and (c) DR4 may protect from virus B persistence. Identification of adventitious factors such as delta may help uncover a subgroup of HBsAg carriers who are genetically predisposed to develop chronic liver disease.

Thirteen children who had repeated liver biopsies over a period of 2-16 years after the onset of papular acrodermatitis (PAC) were studied retrospectively. Six patients, rebiopsied within 36 months after the onset of PAC, had histologic evidence of chronic periportal hepatitis. However, repeated biopsies in 3 of the patients revealed a normal liver or chronic portal hepatitis. Whereas all patients had at the end of the observation markers of hepatitis B virus infection, 8 of the 10 patients studied had HBs antigenemia. These data indicate that severe active liver disease may regress without treatment in patients who have had PAC. However, the high frequency of a chronic HBsAg-carrier state among these patients suggests either an inefficient clearance of the virus or an altered immune reaction.

We studied the blood distribution of T and B cells in relation to the etiology and the course of the hepatitis process, in 61 consecutive patients with acute viral hepatitis (AVH). Patients with acute viral hepatitis B showed a significant increase in total T, active T and SmIg cells, lasting the first two weeks of disease. These alterations disappeared in patients with resolving hepatitis. SmIg cells remained persistently elevated in the blood of three patients, who developed chronic hepatitis B. In patients with other types of viral hepatitis, lymphocytes were unaltered, with the exception of a transitory increase in SmIg cells, during the convalescence phase of hepatitis A. The finding that lymphocytes were activated exclusively in patients with acute hepatitis B, but not in those with other types of hepatitis, suggests that the mechanisms of liver injury in hepatitis B may differ from those involved in the pathogenesis of hepatitis A and nAnB.

Hepatitis B virus (HBV) replicating in patients with serum hepatitis B surface antigen and antibody to hepatitis B e antigen (cryptic HBV replication) can be detected by a spot hybridization technique for serum HBV-DNA and by immunoperoxidase staining of hepatitis B core antigen in the liver. These methods allowed us to study the effects of chronic (13 to 82, mean 30 months) administration of low doses (10 or 15 mg/day) of prednisone to 17 patients with chronic active hepatitis and cryptic HBV replication. Liver biopsies performed before treatment demonstrated that 1 to 50% (mean 12%) of the liver cells were infected. After therapy, infected cells had disappeared in 5 (29%), were considerably reduced in 9 (53%) and remained unchanged in 3 (18%) patients. The mean percentage of infected cells in the liver biopsies performed at the end of the follow-up was 3.2 +/- 5.5% (p less than 0.005). Serum HBV-DNA was present in 12 of 13 and in 5 of 12 patients investigated before treatment and at the end of the study, respectively. Five patients harboring HBV in the liver developed cirrhosis during treatment. Our data indicate that, despite steroid therapy, HBV replication either ceased or was decreased in two thirds of the patients, while in no case it flared-up. The rise of cirrhosis was not prevented by this type of therapy.

Two hundred and forty household contacts of 85 chronic HBsAg carriers were studied to assess the relationship between liver histology and 'e' antigen or antibody positivity in the index carrier, and evidence of HBV infection within the family. Liver biopsy results were available in 54 index carriers. The prevalence of HBsAg and anti-HBs in the families of 29 carriers with chronic hepatitis and 25 carriers with either a normal liver or minimal inflammatory changes was not significantly different. Serum from 72 index carriers was available for HBeAg and anti-HBe testing. The prevalence of HBsAg and anti-HBs in the families of 5 HBeAg positive carriers, 59 anti-HBs positive subjects, and 8 carriers negative for both HBeAg and anti-HBe was again not significantly different. Infectivity of a carrier thus does not appear to correlate either with histological evidence of liver damage or with the 'e' antigen or antibody positivity of the carrier.

Horizontal transmission of hepatitis B virus (HBV) from illicit drug users to their contacts, including young children, can be prevented by active immunization against HBV. Yeast-recombinant hepatitis B vaccines are now available for this purpose, but their potential efficacy in such high-risk contacts has not yet been evaluated. Therefore we gave 20 mcg of a recombinant yeast-derived hepatitis B vaccine to 38 children who were at high risk for HBV infection because they had been institutionalized in a community for drug users in which 8.7% of the occupants are carriers. After third dose of vaccine (at 0, 1, and 6 months), all children had anti-HBs responses with titers of 10 mIU/ml or more, with 81% showing responses greater than 1,000 mIU/ml. At 12 months, the percentage of anti-HBs-positive children was 100%, and the percentage of children with anti-HBs higher than 1,000 mIU/ml was 56%. None of the children developed HBV infection during follow-up. Hence the recombinant vaccine was immunogenic, with percentages of seroconversion and anti-HBs titers comparable with those attained in other categories of high-risk children with plasma-derived vaccines.