The role of pre-core hepatitis B virus mutants on the long-term outcome of chronic hepatitis B virus hepatitis. A longitudinal study

doi:10.1016/S0168-8278(05)80149-7

Journal of Hepatology

Volume 20, Issue 6, 1994, Pages 773-781

https://doi.org/10.1016/S0168-8278(05)80149-7 Get rights and content

To define the relationship between pre-core hepatitis B virus mutants and the long-term outcome of chronic hepatitis B virus infection, we monitored the type of circulating pre-core hepatitis B virus-DNA by polymerase chain reaction and sequencing in 41 selected chronic HBsAg carriers with extensive follow up. They included 12 HBeAg-positive patients with chronic hepatitis, who seroconverted to anti-HBe during follow up and 29 anti-HBe positive patients, 23 of whom had chronic hepatitis and six acute severe exacerbation occurring spontaneously (three cases) or during antitumor chemotherapy (three cases). In the presence of HBeAg, all showed prevalence of the pre-core wild type along with high levels of viral replication and elevated alanine aminotransferase. Anti-HBe seroconversion was accompanied by a dramatic reduction of hepatitis B virus replication and normalization of alanine aminotransferase in all, except one, and by the emergence of mutated strains with a pre-core stop codon (point mutation G to A at nt 1896) that replaced the wild type in seven of the 12. Of the seven who harboured the pre-core mutant, three continued to show normal alanine aminotransferase during subsequent follow up, three had mild alanine aminotransferase elevation and one had an acute short-lived reactivation after 4.4 years of normal alanine aminotransferase. The five cases who continued to show prevalence of wild type in spite of anti-HBe seroconversion all revealed persistently normal alanine aminotransferase. Of the 29 anti-HBe positive patients, two (7%) were infected predominantly by wild type pre-core, two (7%) showed a mixed viral population consisting of pre-core stop codon and wild type strains, while 25 (86%), including the six with acute reactivation, revealed prevalence of pre-core defective strains. Since it was observed in 23 cases, the predominant pre-core defect was the stop codon reported above, associated with a mutation (also G to A) at nt 1899 in 12. A point mutation at nt 1814 (A to C) that eliminated the pre-core start codon was detected in two cases. Anti-HBe-positive patients with a prevalence of precore mutants had more severe or progressive liver disease compared with those who were predominantly infected with wild type or mixed viral populations. This study confirmed that, after seroconversion to anti-HBe and emergence of precore mutants, two outcomes are possible: either asymptomatic normal alanine aminotransferase/HBsAg carrier state or ongoing liver disease. However, anti-HBe-positive patients with the most severe form of chronic hepatitis are infected predominantly with pre-core hepatitis B virus mutants.

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Cited by (46)

Therapeutic strategies in the management of patients with chronic hepatitis B virus infection
2008, The Lancet Infectious Diseases
Citation Excerpt :
HBeAg-negative chronic hepatitis B may develop immediately after the HBeAg seroconversion phase or after several years of an inactive chronic carrier state.11 It is associated with emergence of HBV strains that replicate but do not express HBeAg,19 and is more likely to run a fluctuating course, leading to cirrhosis and decompensation.11,20,21 In general, chronic HBV infection is characterised by its dynamic natural course, which includes apparent periodic activation of the host immune system against the infected hepatocytes to eradicate the virus, but this activation usually causes disease exacerbations and leads to the accumulation of fibrosis and development of cirrhosis.9,10
Currently available options for the treatment of chronic hepatitis B virus (HBV) infection include standard and pegylated interferon alfa and four oral antiviral agents (lamivudine, adefovir, entecavir, and telbivudine). These treatment strategies are either therapies of finite duration that aim to achieve sustained off-therapy responses, or long-term treatments that aim to maintain on-therapy remission. Pegylated interferon alfa may offer higher sustained off-therapy responses after 1 year, but most patients do not respond. Oral antivirals are the only candidates for long-term treatment of patients with chronic HBV infection. Viral suppression has favourable effects on patients' outcome and modifies the natural history of the disease. Viral resistance is the main drawback of long-term antiviral therapy. Lamivudine monotherapy is associated with higher resistance (year 1, 10–27%; year 2, 37–48%; year 4, 60–65%) than adefovir (year 1, 0%; year 2, 3%; year 5, 29%) or telbivudine (year 1, 3–4%; year 2, 9–22%). Entecavir resistance is rare in naive individuals (year 4, <1%), but increases over time in lamivudine-resistant patients (year 4, 43%). The best strategy for long-term therapy in chronic HBV infection has yet to be established.
Natural history of hepatitis B virus infection: An update for clinicians
2007, Mayo Clinic Proceedings
Citation Excerpt :
In such patients, serum HBV DNA levels may increase only transiently before serum ALT levels increase.85 In general, HBeAg-negative chronic hepatitis represents a potentially severe and progressive form of chronic liver disease.88,89 Because most, if not all, of these patients have gone through the HBeAg-positive chronic hepatitis phase, varying degrees of hepatic fibrosis are already present.
Hepatitis B virus (HBV) is a common viral pathogen that causes a substantial health burden worldwide. Significant progress has been made in the past few decades in understanding the natural history of HBV infection. A dynamic balance between viral replication and host immune response is pivotal to the pathogenesis of liver disease. In immunocompetent adults, most HBV infections spontaneously resolve, whereas in most neonates and infants they become chronic. Those with chronic HBV may present in 1 of 4 phases of infection: (1) in a state of immune tolerance, (2) with hepatitis B e antigen (HBeAg)-positive chronic hepatitis, (3) as an inactive hepatitis B surface antigen carrier, or (4) with HBeAg-negative chronic hepatitis. Of these, HBeAg-positive and HBeAg-negative chronic hepatitis may progress to cirrhosis and its long-term sequelae including hepatic decompensation and hepatocellular carcinoma. Several prognostic factors, such as serum HBV DNA concentrations, HBeAg status, serum aminotransferases, and certain HBV genotypes, have been identified to predict long-term outcome. These data emphasize the importance of monitoring all patients with chronic HBV infection to identify candidates for and select optimal timing of antiviral treatment, to recognize those at risk of complications, and to implement surveillance for early detection of hepatocellular carcinoma.
Validation and comparison of different PCR-based methods for detection of hepatitis B virus precore region mutants
2005, Journal of Virological Methods
Hepatitis virus variants detection is useful in clinical practice; however, methods that are used for their identification may influence the results significantly. Three PCR-based assays for quantitation of G1896A precore HBV mutants: two allele specific PCRs, single tube (single-AS-PCR) with enzymatic restriction or separate tubes (twin-AS-PCR) and one oligohybridization assay (OA) with three probes were developed and standardized. Wild type and mutant plasmids and 10 sera were used as reference. All methods had sensitivity limits of 10⁴ copies/ml and their specificity encompassed 3 logs (10⁴–10⁷ copies/ml) with dynamic ranges of logs for OA, twin-AS-PCR and single-AS-PCR, respectively. Single-AS-PCR and OA detected minor viral populations when their relative prevalence was at least 10% of the overall viral population whereas their detection by twin-AS-PCR ranged from 0.1 to 10% for samples with 10⁷ and 10⁵ copies/ml viral loads, respectively. Twin-AS-PCR was the most sensitive to detect the minor viral population, whereas single-AS-PCR and OA were more accurate to quantify the relative proportions of the two viral populations independently of the overall viral load. In conclusion, an accurate characterization of HBV precore heterogeneity should be warranted by a careful choice of the most appropriate assay according to the aim of the study.
Basal core promoter mutations of hepatitis B virus increase the risk of hepatocellular carcinoma in hepatitis B carriers
2003, Gastroenterology
Background & Aims: Hepatitis B viral (HBV) genotype C is associated with the development of hepatocellular carcinoma (HCC) compared with genotype B; however, the virologic factors contributing to the pathogenic differences remain unknown. We investigated the prevalence of T1762/A1764 basal core promoter mutant in a cohort of 250 genotype B- or C-infected HBV carriers with different stages of liver disease to clarify a possible role for this mutant in hepatocarcinogenesis. Methods: The sequences of basal core promoter of HBV genome were determined in 60 inactive HBV carriers and 190 patients with histologically verified chronic liver disease and HCC. Results: Genotype C has a higher prevalence of T1762/A1764 mutation than genotype B (odds ratio, 5.18; 95% confidence interval [CI], 2.59–10.37; P < 0.001). The likelihood of T1762/A1764 mutation parallels the progression of liver disease, from 3% in inactive carriers to 64% in HCC patients (odds ratio, 20.04; 95% CI, 7.25–55.41; P < 0.001). By multiple logistic regression analysis, patients with T1762/A1764 mutation were significantly associated with the development of HCC than those without (odds ratio, 10.60; 95% CI, 4.92–22.86; P < 0.001), and the risk was observed for both genotypes B and C. In addition, the prevalence of T1762/A1764 mutation in younger HCC patients was comparable with older HCC patients but was significantly higher than that in age-matched inactive carriers, irrespective of genotypes. Conclusions: Our data suggest that HBV carriers with T1762/A1764 basal core promoter mutant are at increased risk for HCC and that this mutant may contribute to the pathogenesis of HBV infection.
Viral genotype and hepatitis B virus DNA levels are correlated with histological liver damage in HBeAg-negative chronic hepatitis B virus infection
2002, American Journal of Gastroenterology
Citation Excerpt :
These HBV mutants have been reported to be associated with fulminant hepatitis (4–7), chronic active hepatitis (8, 9), and hepatocellular carcinoma (10–12) among HBeAg-negative patients. However, others, including our group, have found these HBV mutants in a large number of HBeAg-negative patients who had inactive liver disease (13–17). Whether core promoter/precore stop codon mutations cause more severe liver damage has always been a contentious issue.
OBJECTIVES:
We aimed to study the relationship between the hepatitis B virus (HBV) genotypes, core promoter/precore stop codon mutations, and histological liver damage among hepatitis B e antigen (HBeAg)-negative patients.
METHODS:
Liver biopsy specimens of 55 HBeAg-negative chronic HBV-infected patients were studied. A histological activity index was scored for degree of necroinflammation (HAI-NI) and fibrosis (HAI-F) as described by Knodell et al. HBV DNA was determined by a cross-linking assay and polymerase chain reaction (PCR) at the core promoter/precore region and the S region. PCR-positive samples were directly sequenced for core promoter and precore mutations and examined by restriction fragment length polymorphism for genotyping.
RESULTS:
Forty-one males and 14 females at a median age of 43 were studied. HBV DNA was detectable in 32 (58%) and 37 (67%) patients by the cross-linking assay and PCR, respectively, at the time of liver biopsy. The median (range) HAI-NI and HAI-F scores were 5 (1–10) and 2 (0–4), respectively. HBV DNA detectable by either the cross-linking assay or PCR was associated with a higher HAI-NI score. Eleven and 31 patients had genotypes B and C HBV, respectively. Genotype C HBV was associated with higher HAI-NI than genotype B HBV. Core promoter mutations and precore stop codon mutation were detected in 74% and 40% patients, respectively, but they were not associated with higher HAI-NI or HAI-F scores.
CONCLUSIONS:
Detectable HBV DNA and genotype C HBV, but not core promoter or precore stop codon mutations, are associated with more severe liver damage in HBeAg-negative patients.
Mutant hepatitis B viruses: A matter of academic interest only or a problem with far-reaching implications?
2001, Vaccine

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Regular PaperThe role of pre-core hepatitis B virus mutants on the long-term outcome of chronic hepatitis B virus hepatitis. A longitudinal study

Lancet

Gastroenterology

Gastroenterology

Gastroenterology

Blood

Virology

Seroconversion from hepatitis B e antigen to antibody in chronic type B hepatitis

Ann Intern Med

Analysis of liver disease, nuclear HBcAg, viral replication and hepatitis B virus DNA in liver and serum of HBeAg vs anti-HBe positive carriers of hepatitis B virus

Hepatology

Mutation preventing formation of hepatitis B e antigen in patients with chronic hepatitis B infection

Lancet

Identification of HBV variants which cannot produce precore derived HBeAg and may be responsible for severe hepatitis

Ital J Gastroenterol

Hepatitis B virus with precore region defects prevail in persistently infected hosts along with seroconversion to the antibody against e antigen

J Virol

Regular Paper
The role of pre-core hepatitis B virus mutants on the long-term outcome of chronic hepatitis B virus hepatitis. A longitudinal study