Distinguishing between acute and symptomatic chronic hepatitis B virus infection

BACKGROUND/AIMS: Differentiating between an acute hepatitis B (AH-B) infection and an acute exacerbation of a chronic hepatitis B (CH-B) infection can present a problem for the clinician. The only current serological method of distinguishing between acute and symptomatic chronic hepatitis B virus (HBV) infection is the immunoglobulin M antibody to hepatitis B core antigen (anti-HBc) assay, which can be problematic. Therefore, in an attempt to better distinguish between acute and chronic HBV infection, sera from 26 patients with AH-B and 53 patients with CH-B were compared in a variety of experimental immunoassays. METHODS: Experimental assays have been designed to detect free antibody to hepatitis B e antigen (anti-HBe), hepatitis B e antigen (HBeAg)/anti-HBe immune complexes (ICs), and hepatitis B surface antigens (HBsAg)/antibody to hepatitis B surface antigen (anti-HBs) in the presence of excess antigen. An additional assay was developed to detect a novel anti-HBc specificity, designated antibody to woodchuck hepatitis virus (anti-HBcW), which cross-reacts with the core antigen of the woodchuck hepatitis virus. RESULTS: Sera from patients with CH-B showed significantly higher levels of free anti-HBe, HBeAg/anti-HBe ICs, and HBsAg/anti-HBs ICs compared with AH-B patient sera. Furthermore, patients with CH-B consistently produced high titer anti-HBcW, whereas patients with AH-B produced little or no anti-HBcW antibody. CONCLUSIONS: The serology of AH-B infection and symptomatic CH-B infection can be distinguished using a variety of experimental immunoassays in addition to the immunoglobulin M anti-HBc assay.     

Fibrosing cholestatic hepatitis in a transplant recipient with hepatitis B virus precore mutant

A patient with hepatitis B virus (HBV) precore mutant (seropositive for hepatitis B surface antigen [HBsAg], anti-hepatitis B e antigen [HBeAg], and HBV DNA) who underwent orthotopic liver transplantation for end-stage liver disease is described. Sequencing of the HBV precore region of the pretransplant serum sample confirmed the presence of the precore stop-codon mutant (G-->A mutation in codon 1896) only. The patient received HBV immunoglobulin prophylaxis for 6 months but HBV recurred thereafter with a mild hepatitic flare, and he remained seropositive for HBsAg, anti-HBe, and HBV DNA. The initial hepatitic illness resolved in 3 months. The patient remained well for another 16 months before presenting with fibrosing cholestatic hepatitis (FCH). During his entire initial hepatitic flare, quiescent period, and final FCH phase, he remained seropositive for HBsAg, anti-HBe, and HBV DNA. Moreover, sequencing of the serum HBV DNA in final FCH phase showed the presence of the identical HBV precore mutant. Immunohistochemical staining showed extensive expression of HBsAg/pre-S1, pre-S2, and hepatitis B core antigen, but HBeAg was scarcely detectable. This case illustrates that (1) recurrence of HBV precore mutant infection can occur in liver; (2) it can give rise to FCH; and (3) hepatic accumulation of HBeAg is not essential for the development of FCH.     

Nested polymerase chain reaction (PCR) and multiple cloned antibody capture PCR for the examination of serum hepatitis B virus DNA in negative hepatitis B surface antigen patients suffering from liver diseases

In order to find out rapidly the causes of the liver diseases suffered by patients with negative hepatitis B surface antigen (HBsAg), nested polymerase chain reaction (PCR) and multiple cloned antibody capture PCR techniques were established to examine serum hepatitis B virus (HBV) DNA. By using both techniques along with the examination of hepatitis C virus (HCV) infection, the causes of chronic liver diseases with negative HBsAg were studied. It is found that nested-PCR can increase the sensitivity of single PCR more than 1,000 fold and multiple cloned antibody capture-PCR can detect concentration of HBV DNA as low as 0.1-0.01 pg/L. HBV DNA positive patients were found in 45.5%, 30.8%, 13.3% and 100% respectively of the patients suffering from liver cirhosis with negative HBsAg (group A, 22 cases), chronic hepatitis with negative HBsAg (group B, 13 cases), normal subjects with negative HBsAg and positive hepatitis B core antibody (HBcAb, group C, 30 cases) and liver cirhosis with positive HBsAg and negative HBeAg (group D, 12 cases). HBV DNA can be also found in the serum of HBsAb positive patients and subjects supposed to be healthy, 81.8% and 53.8% of the patients were infected with HBV and/or HCV in group A and group B respectively. All these results suggest that nested-PCR and multiple cloned antibody capture-PCR are rapid and highly sensitive methods for detection of serum HBV DNA. HBV infection is an important cause of chronic liver diseases in patients with negative HBsAg. The causes of most of the HBsAg-negative chronic liver diseases are related with infection of viruses. The clinical significance of serum HBsAb in naturally infected patients should be reconsidered.     

A randomized, controlled trial of a 24-month course of interferon alfa 2b in patients with chronic hepatitis B who had hepatitis B virus DNA without hepatitis B e antigen in serum

Short-term interferon treatment of serum hepatitis B e antigen (HBeAg)-negative carriers with serum hepatitis B virus (HBV) DNA and histological features of chronic hepatitis B has been largely unsuccessful. In a pilot study of long-term treatment, 42 such patients were randomly assigned to 6 million units of interferon alfa 2b (IFN-alpha2b) three times per week for 24 consecutive months (n = 21, 4 with cirrhosis) or to no therapy (n = 21, 3 with cirrhosis). Five patients (24%) discontinued therapy because of treatment-related adverse reactions. Serum levels of alanine transaminase (ALT) became persistently normal and HBV DNA undetectable by dot-blot assay in 8 patients receiving interferon and in 2 untreated controls (38% vs. 10%; P = .03). Hepatitis flare-ups disappeared in 17 patients during therapy compared with 6 controls (81% vs. 29%; P < .001). During a median period of 22 months after interferon was stopped, 2 treated patients (10%) lost serum hepatitis B surface antigen (HBsAg) and seroconverted to antibodies to hepatitis B surface antigen (anti-HBs). Serum ALT remained persistently normal and HBV DNA undetectable by dot-blot assay in 6 initial responders and 1 initial nonresponder, compared with none of the 21 untreated controls (sustained response: 33% vs. 0; P < .001). Comparative analysis of pre- and posttreatment liver biopsies showed that mean Knodell scores dropped in the treated group (10.3 to 5.3; P = .01), but not in the untreated group (9.3 to 9.8; not significant). In conclusion, a 24-month course of treatment with 6 MU IFN-alpha2b was well tolerated by most patients, led to sustained suppression of HBV in one third, and attenuated hepatitis in 81% of patients.     

Variations of hepatitis B virus core gene sequence in Western patients with chronic hepatitis B virus infection

Heterogeneity of the hepatitis B virus (HBV) core gene has been reported to be associated with the presence of active liver disease in Japanese patients with chronic HBV infection. This study evaluated the significance of HBV core gene heterogeneity in Western patients with chronic HBV infection. The hepatitis B virus precore/core gene from 45 patients (inactive:active liver disease ratio 16:29) was amplified from serum by polymerase chain reaction (PCR). Gel electrophoresis was employed to detect large deletions. The PCR amplicons from 13 patients (all HBV serotype adw but with a different spectrum of liver disease) were cloned and sequenced. Hepatitis B surface antigen (HBsAg) serotypes were tested by enzyme immunoassay (EIA) and hepatic expression of HBV antigens was assessed by immunohistochemistry. The HBV core gene was amplified from the serum of all 45 patients. Three patients had mixed infection with both precore mutant and wild-type HBV and all three had active liver disease. No patient had a large deletion of the HBV core gene. Hepatitis B virus core gene sequence variations were more common in the midcore region and there was no difference in the number of silent and missense substitutions between those with inactive and active liver disease. There was no correlation between the nucleotide or encoded amino acid substitutions and the clinical and biochemical parameters, including the subsequent response to interferon-alpha therapy (n = 37) or hepatic HBV antigen expression. Variation of the HBV core gene was not found to be preferentially associated with active liver disease in Western patients with chronic HBV infection. The pattern of hepatitis B core gene variation is in accord with the genomic organization of HBV.     

Genetic immunization of chimpanzees chronically infected with the hepatitis B virus, using a recombinant retroviral vector encoding the hepatitis B virus core antigen

Cytotoxic T lymphocyte (CTL) activity and CD4+ helper T cell responses to the hepatitis B virus (HBV) core antigen (HBcAg) have been implicated in clearance of acute and chronic HBV infections. We showed that intramuscular injections of a novel recombinant retroviral vector expressing an HBcAg-neomycin phosphotransferase II (HBc-NEO) fusion protein induces HBc/eAg-specific antibodies and CD4+ and CD8+ T cell responses in mice and rhesus monkeys. We have now immunized three chronically infected chimpanzees, each with 10(10) CFU of nonreplicating retroviral vector particles expressing the HBc-NEO fusion protein. Of two immunized chimpanzees examined for CTL responses, one developed HBcAg-specific CTLs and showed marginal, transient elevations of alanine aminotransferase (ALT) levels following injection. However, both chimpanzees remained positive for serum HBeAg, negative for anti-HBe antibody by conventional assays, and displayed no change in HBV viral load throughout the study. In contrast, the third chimpanzee exhibited a traditional seroconversion evidenced by a loss of serum HBeAg and the subsequent emergence of anti-HBe antibodies within 24 weeks after the first injection. Simultaneously, two transient ALT flares and a significant decrease in the serum HBV DNA levels were noted. Despite its limitations, the present study demonstrates (1) the safety of treatment with high titers of retroviral vector in chimpanzees, (2) the capability of a retroviral vector expressing HBcAg to stimulate immune responses in HBV chronic carrier chimpanzees, and (3) that retroviral vector immunization may be therapeutically beneficial in the treatment of chronic HBV infection.     

Perinatal transmitted acute icteric hepatitis B in infants born to hepatitis B surface antigen-positive and anti-hepatitis Be-positive carrier mothers

Three infants born to mothers who were hepatitis B surface antigen (HBsAg) positive and had antibody to hepatitis Be antigen (anti-HBe), developed acute icteric hepatitis B within three months of birth. All three infants clinically recovered and developed circulating anti-HBs. Contrary to previous studies, these three cases indicate that mother-infant transmission of the hepatitis B virus (HBV) does occur in infants born to HBsAg-positive, HBe-Ag-negative carrier mothers, and these infants may develop severe acute icteric hepatitis. Therefore, immunoprophylaxis in such newborns may be indicated.     

Dane particle-associated DNA polymerase and e antigen: relation to chronic hepatitis among carriers of hepatitis B surface antigen

Thirty-nine carriers of hepatitis B surface antigen (HBs Ag) were studied with respect to e antigen and Dane particle-associated DNA polymerase activity and their relation to chronic hepatitis. Most of these individuals were followed for four or five years. A strong correlation between e antigen and DNA polymerase activity was found. Of the 22 e antigen-positive patients, 21 showed polymerase activity; none of the 13 e antigen-negative patients (one of whom had antibody to e antigen) had such activity. Three of four patients who became e antigen-negative after being e antigen-positive showed loss of polymerase activity. An independent clinical evaluation showed a strong correlation between chronic hepatitis and positive reactions in the tests for e antigen and DNA polymerase. The results emphasize the possibility of differentiating between groups of chronic carriers of HBs Ag by testing for e antigen and Dane particle-associated DNA polymerase activity. The differentiation may have important clinical implications.     

Long-term hepatitis B vaccine in infants born to hepatitis B e antigen positive mothers

Neonates of hepatitis B surface antigen (HBsAg) positive and hepatitis B encoded antigen (HBeAg) positive mothers received 10 micrograms of recombinant hepatitis B vaccine at months 0, 1, 6, or 0, 1, 2, 12, with or without immunoglobulin at birth, and were followed up to the age of 8 years for HBsAg, anti-HBc, and anti-HBs. Some were boosted at month 60. The overall vaccine protection at month 12 was 96.2%. No child became a chronic carrier beyond the age of 3 years, showing that this vaccine provides immediate protection against HBsAg carriage, and long term protection against fetally acquired HBsAg. After month 60 hepatitis B serological markers without disease, indicating re-exposure to HBV, reappeared in comparable numbers among boosted and non-boosted children (5 for a total of 167 children). This vaccine provides long-term protection against hepatitis B chronic carriage and infection in high risk neonates with or without a month 60 booster. A booster at the age of 5-6 years or 11-12 years would reduce HBV infection, viral circulation and transmission, while ensuring long-term antibody persistence.     

Response of patients with dual hepatitis B virus and C virus infection to interferon therapy

Patients with dual infection with hepatitis B virus (HBV) and delta virus (HDV) responded poorly to interferon (IFN) therapy. Little is known about the effect of IFN therapy in patients with HBV and hepatitis C virus (HCV) dual infection. The patients in two randomized controlled trials with chronic HBV infection were retrospectively assayed for HCV markers. The HBV responses to IFN therapy in patients with and without HCV markers were compared. An open trial was conducted in 4 patients who had lost their serum HBV surface antigen (HBsAg) but had continuing HCV viremia and hepatitis. Of the 15 patients seropositive for HCV marker(s), only 1 (6.7%) responded with seroclearance of HBV DNA and HBV e antigen, as compared with 46 (28%) of 164 HCV-negative patients (p = 0.058). Icteric hepatitis developed in 1 patient on emergence of serum HCV RNA in association with seroclearance of HBV DNA. In contrast, good response was demonstrated in 3 of the 4 patients who had lost serum HBsAg before therapy. The results suggest that IFN therapy is not only of limited value in patients with dual infection with HBV and HCV but also has a potential risk of severe hepatitis if the clearance of one virus removes its suppressive effect on and facilitates the emergence of the other. However, patients with continuing HCV hepatitis after termination of the chronic HBsAg carrier state responded well to IFN therapy.     

The prevalence of HBsAg in hospitalized children as a marker of hepatitis B virus infection]

The aim of this study was to determine the prevalence of hepatitis B surface antigen (HBsAg) in hospitalised children, as specific marker for hepatitis B virus (HBV) infection. Our study group consists of 517 children, 68 of them diagnosed with chronic hepatitis. For HBsAg determination we used an ELISA test (Labsystems); for some children we also tested by ELISA the following markers: the antibodies and anti-hepatitis C virus (HCV) antibodies. From 517 children 24.28% were HBSAg positive and 75% of children with chronic hepatitis were positive for the same marker. Almost 100% of chronic active hepatitis (CAH) patients was positive for HBSAg. CONCLUSIONS: 1. The prevalence of HBsAg was much higher as compared with the healthy population prevalence; it is a clear prove that HBV infection has an important role in chronic hepatitis appearance. 2. For all HBsAg positive patients, it is necessary to determine other markers like HBeAg-anti-HBe antibodies system as well as markers for other viral hepatitis (HDV, HCV). 3. The anti-HBV infection vaccine will reduce significantly the prevalence of HBV and HDV infections; 4. Biological molecular technique, like PCR will be necessary in our country, in the future, even the price is so high, to monitoring the IFN treatment for chronic infection as unique solution for these patients.     

Clinical and histological outcome after hepatitis B e antigen to antibody seroconversion in children with chronic hepatitis B

Data regarding the outcome of children with chronic hepatitis B after seroconversion are scarce. We describe the long-term evolution of these patients. One hundred and three children with antibody against hepatitis B e antigen and normal alanine aminotransferase (ALT) levels were followed for 0.6 to 12.5 years (mean, 6.3 years). Paired liver biopsies (before and after seroconversion) were available in 83 cases. Final biopsies were obtained 0.5 to 12.5 years (mean, 4.5 years) after seroconversion. ALT levels remained normal in most of the children (79%) throughout the follow-up. All children, except five who lost hepatitis B surface antigen, had serum viral DNA detected by polymerase chain reaction. When comparing baseline and final liver biopsies, a significant improvement (P <.001) was found in the histological activity index and in the necrosis, cytolysis, inflammation, and fibrosis scores. The histological diagnosis improvement in the final biopsy was significantly related (P <.001) to the time from seroconversion to the biopsy performance. All children had viral DNA on their final liver biopsy. In summary, seroconversion and ALT normalization are quite stable findings in children, and no differences in the long-term outcome between treated and untreated children were found. In light of the histological outcome, it seems unnecessary to perform a follow-up liver biopsy in these cases.     

Use of quantitative assays for hepatitis B e antigen and IgM antibody to hepatitis B core antigen to monitor therapy in chronic hepatitis B

OBJECTIVES: We evaluated the clinical utility of IgM antibody to the hepatitis B (HB) core antigen (anti-HBc) and HB e antigen (HBeAg) serum levels in patients with chronic HB receiving interferon alfa. METHODS: Stored serum from 47 patients with chronic HB participating in a controlled trial of interferon alfa therapy (10 million U three times a week for 16 wk) were analyzed. All were seropositive for HB surface Ag, HBeAg, and HB virus (HBV) DNA before entry. IgM anti-HBc index values and HBeAg standard values were determined by automated microparticle enzyme immunoassay on samples drawn just before therapy and 6 months later. Ten normal subjects were tested as controls. IgM anti-HBc and HBeAg levels were compared to initial serum HBV DNA, DNA polymerase, serum aminotransferase levels, and demographic features. Serial IgM anti-HBc levels were also obtained during and after therapy in 10 responders and five nonresponders, and serial HBeAg levels were also obtained during and after therapy in four responders and four nonresponders. RESULTS: Neither IgM anti-HBc nor HBeAg levels correlated significantly with values for serum HBV DNA, DNA polymerase, aminotransferases, or demographic features. The initial mean IgM anti-HBc level among the 15 responders to therapy (loss of HBeAg and HBV DNA from serum) was no different from that in nonresponders (mean 1.15 vs 1.27, p = not significant). However, the initial mean HBeAg level was significantly lower in responders than in nonresponders (749.4 vs 1356.4, p = 0.019). Among 10 responders, IgM anti-HBc levels decreased progressively over time, so that at latest follow-up (1.5-4 yr later, mean 2.6 yr), the mean had decreased from 1.325 to 0.312 (p = < 0.001). Among five nonresponders, the mean did not change significantly over 1.5-3 yr (mean 2.2 yr) (1.26 vs 1.08, p = not significant). HBeAg values fell in parallel with HBV DNA and DNA polymerase values in four responders tested but remained elevated in four nonresponders. CONCLUSIONS: HBeAg levels, but not IgM anti-HBc levels, are useful in predicting response to interferon alfa, with responders tending to have lower pretreatment HBeAg levels than nonresponders. HBeAg levels may be used to monitor response to interferon alfa in patients with chronic HB.     

Chronic hepatitis B and C in HIV-infected patients

BACKGROUND AND AIM: This retrospective study examined the prevalence of co-infections with hepatitis B virus (HBV) and hepatitis C virus (HCV) and the frequency of chronic hepatitis in HIV-infected patients with respect to both the different risk groups and the serological results. PATIENTS AND METHODS: All Zurich participants of the Swiss HIV Cohort Study were evaluated who had available results of hepatitis B and C serology and ALT. RESULTS: Of the total 279 patients, 52% belonged to the intravenous drug user, 34% to the homosexual, and 11% to the heterosexual risk category. Serologically, previously acquired infection with HBV alone could be demonstrated in 92 (33%), HCV alone in 9 (3%), and both HBV and HCV in 130 (47%) patients. Only 3% of patients with sexually acquired HIV infection had anti-HCV antibodies, whereas co-infection with HBV and HCV was present in 87% of intravenous drug users. Among the 222 patients with previous HBV contact, 25 (11%) had positive HBsAg and 91 (41%) had "anti-HBc alone", both assumed to represent active HBV infection. 66 (24%) of 279 patients had chronic hepatitis with ALT elevation lasting > or = 6 months. Chronic hepatitis was present in 46% of those with active HBV and HCV co-infection, in 36% of those with HCV infection alone and in 18% of those with active HBV infection alone (P < 0.001). Of the 66 cases of chronic hepatitis, 58 were associated with HCV infection, and only 2 cases had no serological signs of active HBV or HCV infection. CONCLUSION: In patients with sexually acquired HIV infection, HBV had frequently been co-transmitted. In contrast, almost all of those infected by means of intravenous drug use had a co-infection with both HBV and HCV. The latter seems to play the strongest role in the development of chronic hepatitis with persistent ALT elevation. A chronic ALT elevation was almost always associated with serologically active HBV or HCV infection.     

Chronic hepatic porphyria and hepatitis B and C virus infections

BACKGROUND: It is known that in patients with porphyria cutanea tarda (PCT) there is an increased prevalence of the hepatitis B virus (HBV) and the hepatitis C virus (HCV). The incidence of anti-HCV in PCT in our country is 21.7% in estimations by the second generation method, however, the incidence of HBV in PCT was not assessed so far. METHODS AND RESULTS: In 60 patients with PCT antigens and antibodies against HBV and HCV were assessed (by the anti-HCV third generation ELISA method) and in subjects with signs of HBV or HCV. HBV DNA and HCV RNA were assessed by the method of the polymerase chain reaction. PCT without detectable HBV or HCV infection was found in 45 subjects (68%). HBV infection only was confirmed in seven subjects (10.6%), however none of the patients had positive HBsAg in serum. All had only antibodies against HBV. HCV infection only was detected in seven patients (10.6%) and HBV and HCV co-infection also in seven patients (10.6%). In the group of patients with HBV and HCV co-infection there was not a single HBsAg positive subject. The mean ALT serum activity was significantly higher as compared with subjects with HBV or HCV infection only (p < 0.05) and the histological finding on liver biopsy was more serious. CONCLUSION: HBV (21%) and HCV (21%) infection participates significantly in the clinical picture of PCT. A special subgroup is formed by patients with PCT and HBV and HCV co-infection who have as a rule a higher ALT activity and more severe histological changes in the liver. The incidence of HBV and HCV infection in PCT in the Czech Republic is double as compared with Germany or Great Britain.     

Chronic hepatitis B virus infection in south Auckland

AIM: Previous studies have identified high prevalence rates of hepatitis B infection in New Zealand Maori, Pacific Island and Asian populations within New Zealand. However, the true impact of chronic hepatitis B virus (HBV) infection on health resources has not been evaluated. This study was designed to determine the incidence of serious sequelae of chronic HBV infection in a high prevalence community. METHODS: All patients treated for HBV-related conditions at Middlemore Hospital from January 1995 to January 1997 were identified through discharge coding and laboratory records. Demographic characteristics and laboratory results, including liver function tests, hepatitis serology and liver histology were recorded. Number of admissions, average length of stay and survival were calculated from Casemix data. RESULTS: During the study period, 215 patients were referred for management of hepatitis B infection, of whom 179 had persistently elevated aminotransferases. Forty six percent of patients were hepatitis B 'e' antigen (HBeAg) negative, and 21% of these had delta co-infection (all Samoan). Liver biopsy was performed in 87 patients with raised aminotransferases. No features of chronic hepatitis were found in 5%, mild chronic hepatitis in 30%, moderate to severe chronic hepatitis in 44% and cirrhosis in 22%. Fifty five patients were admitted to hospital during the two year period with an HBV-related diagnosis, with an average length of stay of 12.2 days compared to 4.9 days for all other medical and surgical admissions during this period (p < 0.001). Twenty eight of the 55 subsequently died, 20 from hepatocellular carcinoma. CONCLUSIONS: Chronic hepatitis B infection is associated with significant morbidity and mortality in Maori, Pacific Islanders and Asians living in South Auckland. Screening of these high risk populations with vaccination of noninfected individuals should reduce the incidence of these serious sequelae and eventually lead to eradication of HBV.     

Detection of hepatitis B surface antigen in pregnant women attending a public hospital for delivery: implication for vaccination strategy in Bangladesh

Routine antenatal hepatitis B surface antigen (HBsAg) screening and immunization of risk babies is very effective in preventing perinatal transmission of hepatitis B virus (HBV). We studied 1,800 parturients attending a public hospital to assess the rationale for such vaccination in Bangladesh. In one in every 29 deliveries (63 of 1,800 or 3.5%), the mother was found to be HBsAg positive. All were asymptomatic and many (41 of 63 or 65%) without risk factors would remain undetected if HBsAg screening were performed on selected groups. Most of the HBsAg-positive mothers (54 of 63 or 85.7%) were found to be chronic carriers and 30.2% (19 of 63) were also hepatitis B e antigen (HBeAg) positive, indicating high infectivity. Although 23 cord blood were positive for HBsAg or HBeAg, none were positive for IgM antibody to hepatitis B core antigen (IgM anti-HBc), suggesting transplacental transmission of the antigens rather than intrauterine infection. These findings are discussed in relation to the cost-effectiveness of routine prenatal screening and immunization of risk babies compared with universal infant immunization.     

Recurrence of hepatitis D (delta) in liver transplants: histopathological aspects

BACKGROUND: The viral/pathological correlates of recurrent hepatitis delta virus (HDV) disease in orthotoptic liver transplants are reported. METHODS: We examined the histological features of recurrent HDV disease in nine patients with transplants for terminal HDV cirrhosis were examined; intrahepatic HDV and hepatitis B virus (HBV) antigens were detected by immunoperoxidase techniques. Sera were tested for the battery of HDV and HBV markers. RESULTS: In four patients, HDV reinfection was accompanied by the recurrence of an HBV infection with features of active viral replication. In the other five, HDV reinfection was accompanied by an atypical recurrence of HBV infection without evidence of active HBV replication (no expression of intrahepatic hepatitis B core antigen). In four of the latter patients, the atypical HBV pattern changed during the follow-up into a pattern of active viral replication accompanied by chronic necroinflammation detected during histology. CONCLUSION: The pattern of recurrent HBV infection can influence the pathological aspects of the relapses of HDV disease in liver grafts.