Contribution of low level HBV replication to continuing inflammatory activity in patients with anti-HBe positive chronic hepatitis B virus infection.

Lok, Anna S.; Hadziyannis, S.; Weller, I. V. D.; Karvountzis, M. G.; Monjardino, J; Karayiannis, Peter; Montaño, Luis F.; Thomas, Howard

doi:10.1136/gut.25.11.1283

Cited by 114 publications

(48 citation statements)

References 22 publications

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“…[27][28][29][30] In the present study, we also tried to address changes in serum ALT levels after seroconversion of HBeAg to anti-HBe. For this purpose, a cohort of 78 patients, who seroconverted during follow-up, was evaluated.…”

Section: Discussionmentioning

confidence: 99%

Influence of hepatitis B virus genotypes on the progression of chronic type B liver disease

et al. 2003

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To investigate the hepatitis B virus (HBV) genotype-related differences in the progression of liver disease, 585 patients with chronic HBV infection including 258 with histologically verified chronic liver disease (CLD) and 74 with hepatocellular carcinoma (HCC) were examined. The mean ages of both patients with advanced fibrosis (F3 or F4) and with HCC were significantly older in genotype B than in genotype C patients (P ‫؍‬ .018, P ‫؍‬ .024, respectively). Both the hepatitis B e antigen (HBeAg) negativity rate at biopsy and the cumulative HBe seroconversion rate in patients with CLD were significantly higher in genotype B patients than genotype C patients (P < .01, P ‫؍‬ .022, respectively). Multivariate analysis revealed that genotype B, presence of precore mutation, high ALT levels, and severe histologic activity were independent factors for HBe seroconversion. Among all the biopsyproven CLD patients, the ratio of patients with advanced fibrosis in genotype B was significantly lower than that in genotype C (4/30 vs. 74/224, respectively; P ‫؍‬ .034). This difference was more remarkable in younger patients (<45 years; 1/25 vs. 47/180, respectively; P ‫؍‬ .020), and there was no difference in older patients (>45 years). The distribution of each genotype between CLD and HCC was very similar (B and C: 11.2% and 87.0% vs. 10.8% and 89.2%, respectively). In conclusion, our results suggest that, although the patients with genotype B experience earlier HBe seroconversion, slower progression of liver fibrosis, and slower development of HCC, the life-long risk of progression to advanced fibrosis and development of HCC may not differ among genotypes B-and C-related chronic liver disease. (HEPATOLOGY 2003;37:19-26.)

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Section: Discussionmentioning

confidence: 99%

Influence of hepatitis B virus genotypes on the progression of chronic type B liver disease

et al. 2003

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“…This criterion excludes patients at the unstable stage of HBeAg seroconversion. [94][95][96][97] Second, increased ALT levels, either persistent or intermittent. Third, HBV replication documented by either HBV DNA in the serum and/or HBcAg in the liver.…”

Section: Clinical Aspectsmentioning

confidence: 99%

Hepatitis B e antigen-negative chronic hepatitis B

2001

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Thirty years ago, the diagnosis of chronic hepatitis B (CHB) was thought to require the presence of hepatitis B e antigen (HBeAg), as a reliable and sensitive marker of hepatitis B virus (HBV) replication. 1 Individuals positive for hepatitis B surface antigen (HBsAg) but negative for HBeAg were considered to have nonreplicative HBV infection, and if their liver enzymes were normal or nearly normal they were referred to as asymptomatic or healthy HBsAg or HBV carriers. 2 If, on the other hand, they displayed elevated serum aminotransferases and liver histology indicative of chronic hepatitis, they were generally thought to be suffering from other superimposed or complicating conditions such as hepatitis D virus infection, alcohol-induced, metabolic, autoimmune, drug-induced, or other forms of chronic liver disease. 3 In the early 1980s it became apparent that HBV could replicate in the absence of HBeAg. [4][5][6] Patients from the Mediterranean area, although negative for HBeAg and positive for antibodies to HBeAg (anti-HBe), were reported to have CHB with replicating HBV. 7 The term anti-HBe-positive or HBeAgnegative CHB was then proposed 4 and subsequently became widely accepted. In 1989 the molecular basis of this form of CHB was discovered 8,9 with the identification of HBV mutations preventing HBeAg formation from an otherwise normally replicating HBV. 10,11 With time, it became apparent that HBeAg-negative CHB, initially viewed as an atypical and rare form of CHB mainly restricted in the Mediterranean area, had a much wider geographical distribution and that its frequency was increasing. 12 Its molecular virology and immunology were found to be more complex than initially thought, 13 whereas the selection of precore HBV mutants was shown to be largely determined by the HBV genotype. 14 Mutations abolishing or diminishing HBeAg formation were identified along with changes in other parts of the HBV genome. 14 More recently, the new nucleoside analog, lamivudine, has been used to treat a sizeable number of patients with HBeAg-negative CHB, and important information on its efficacy and the development of resistance has been collected. [15][16][17][18] DEFINITION AND NOMENCLATUREThe term HBeAg-negative CHB defines the condition as disease caused by strains of HBV that are not producing HBeAg. 12 It does not specify the mutations responsible for the lack of HBeAg, i.e., a precore stop-codon mutation, 10 a double basic core promoter (BCP) mutation, or other, 14 and it says nothing about the level of HBV replication. The alternative term "precore mutant CHB," used by some investigators, also does not specify the nature of the precore mutation. In clinical practice, the term HBeAg-negative CHB is appropriate for patients with chronic HBV infection who test negative for HBeAg, are usually positive for anti-HBe, have increased alanine aminotransferase (ALT) levels and display detectable HBV DNA in serum by classical hybridization techniques. 12 Despite the fact that the identification of the underlying mutations in ...

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“…However, in areas with high or intermediate HBV endemicity, viral replication and liver damage persist in about 10% of anti-HBe-positive carriers (2,10,15,23). HBV mutants unable to secrete HBeAg because of translational defects in the precore region have been isolated in these patients (1,4,7,14,36).…”

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confidence: 99%

Precore Stop Mutant in HBeAg-Positive Patients with Chronic Hepatitis B: Clinical Characteristics and Correlation with the Course of HBeAg-to-Anti-HBe Seroconversion

et al. 2002

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This study aimed to investigate the ratios of precore stop mutant (codon 28; TGG to TAG) to total viremia in 53 HBeAg-positive patients with chronic hepatitis B by amplification-created restriction site assays along the course of HBeAg-to-anti-HBe seroconversion. At baseline, 11% had exclusive wild-type hepatitis B virus (HBV), 15% had exclusively precore mutant, and 74% had mixed viral strains. Precore mutant ratios correlated little with age, sex, or HBV DNA levels (all P > 0.1), but correlated modestly with alanine aminotransferase (ALT) levels (P ‫؍‬ 0.05). The intervals from presentation to anti-HBe seroconversion correlated significantly with ALT and precore mutant ratios in univariate analysis but with only precore mutant ratios in multivariate analysis (P ‫؍‬ 0.003). Precore mutant ratios at baseline were significantly higher (P < 0.001) in six patients with persistent high viremia and ALT elevation after anti-HBe seroconversion (group 1) than in 47 with remission (group 2). All group 1 patients had exclusive precore mutant after anti-HBe seroconversion, as did only 14 (30%) of the group 2 patients (P ‫؍‬ 0.003). Among group 2 patients, precore mutant ratios at baseline or after anti-HBe seroconversion showed no significant difference between 34 patients with sustained remission and 13 with relapse. Cirrhosis developed in 50% (5 of 10) of patients with precore mutant ratios >50% at baseline but only in 12% (5 of 43) of those with precore mutant ratios of <50% at baseline (P < 0.05). In conclusion, precore mutant of variable ratios was frequently detected in HBeAg-positive patients with chronic hepatitis B. Precore mutant ratios tended to correlate with ALT levels and anti-HBe seroconversion, but high precore mutant ratios were associated with persistent hepatitis after anti-HBe seroconversion and increased risk of cirrhosis.In the natural history of chronic hepatitis B virus (HBV) infection, seroconversion from HBVe antigen (HBeAg) to its antibody (anti-HBe) is usually accompanied by a decrease in HBV replication and remission of liver disease (18,19,31). However, in areas with high or intermediate HBV endemicity, viral replication and liver damage persist in about 10% of anti-HBe-positive carriers (2,10,15,23). HBV mutants unable to secrete HBeAg because of translational defects in the precore region have been isolated in these patients (1,4,7,14,36). In the great majority of them (Ͼ 90%), an unusual HBV strain was characterized with a G-to-A mutation at nucleotide 1896, which generates a stop codon in the precore sequence (28,32,36). Notably, many recent studies have shown that precore mutant also can be detected in HBeAg-positive patients with chronic HBV infection (5,17,25,27,29). The prevalence of precore mutant and its relative ratio to total HBV in HBeAgpositive patients with chronic HBV infection has varied considerably in the published reports: precore mutant is detected in 0 to 80% of HBeAg-positive patients, and the majority have had coexisting predominant wild-type HBV, but a few even have ha...

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Contribution of low level HBV replication to continuing inflammatory activity in patients with anti-HBe positive chronic hepatitis B virus infection.

Cited by 114 publications

References 22 publications

Influence of hepatitis B virus genotypes on the progression of chronic type B liver disease

Influence of hepatitis B virus genotypes on the progression of chronic type B liver disease

Hepatitis B e antigen-negative chronic hepatitis B

Precore Stop Mutant in HBeAg-Positive Patients with Chronic Hepatitis B: Clinical Characteristics and Correlation with the Course of HBeAg-to-Anti-HBe Seroconversion

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