Low HBeAg Serum Levels Correlate with the Presence of the Double A1762T/G1764A Core Promoter Mutation and a Positive Response to Interferon in Patients with Chronic Hepatitis B Virus Infection

Marrone, Aldo; Zampino, Rosa; Luongo, Gelsomina; Utili, Riccardo; Karayiannis, Peter; Ruggiero, Giuseppe

doi:10.1159/000072431

Cited by 15 publications

(13 citation statements)

References 26 publications

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“…In our study all patients but one showed wild type strain and before treatment had high viraemia and normal ALT values. Low serum HBeAg levels in combination with the double CP mutation A1762T/G1764A has also been associated to a positive response to IFN treatment [31,32]. This concurs with Boni et al [23], who has shown how an HBeAg decrease after lamivudine administration is concomitant with a drop in viraemia and a restoration of the T-cell response.…”

Section: Discussionsupporting

confidence: 54%

Three‐phase sequential combined treatment with lamivudine and interferon in young patients with chronic hepatitis B

Marrone

Zampino

Portella

et al. 2005

Journal of Viral Hepatitis

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Alpha-interferon (IFN) or lamivudine monotherapy are ineffective in treating chronic HBeAg positive patients with high viral load and low alanine aminotransferase (ALT) levels. We investigated whether priming lamivudine treatment might enhance the antiviral and immunostimulant action of lamivudine/IFN combination in young tolerant patients. Eleven chronic HBeAg positive patients received: 100 mg/day lamivudine for 3 months followed by IFN 5 MU/m2/tiw with lamivudine 100 mg/day for 6 months and then lamivudine alone 100 mg/day for 9 months. Quantitative hepatitis B virus (HBV)-DNA was evaluated during treatment and core-promoter, precore and polymerase HBV mutants were detected by direct sequencing at the end of therapy. Serum HBV-DNA levels dropped during lamivudine monotherapy and in combination with IFN. After IFN withdrawal, viraemia transiently increased to high levels in five of 11 (45%) patients who showed rt M204V/I lamivudine mutant resistant. Two patients cleared HBeAg without anti-HBe seroconversion. One patient presented core-promoter (A1762T/G1764A) and precore stop codon mutations. Hence, three-phase sequential combined lamivudine/IFN treatment reduced HBV-DNA serum level, but did not lead to HBeAg and HBV-DNA clearance in these highly viraemic, normal ALT patients. Lamivudine/IFN combination did not prevent the emergence of YMDD lamivudine resistance. New schedules of antiviral treatments must be evaluated in this population at risk of disease progression.

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Section: Discussionsupporting

confidence: 54%

Three‐phase sequential combined treatment with lamivudine and interferon in young patients with chronic hepatitis B

Marrone

Zampino

Portella

et al. 2005

Journal of Viral Hepatitis

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“…The precore/core and promoter regions of HBV have been investigated continuously with emphasis on molecular parameters that would predict the outcome of interferon response on mainly genotypes A and D [Kanai et al, 1996;Erhardt et al, 2000;Marrone et al, 2003]. It has been considered that nucleotide changes within the basal (basic) core promoter (nucleotide regions 1742-1849) might be one of the determinants for maintaining or lowering of precore/core function and the level of HBV replication, because the basal core promoter controls the transcription of precore/core mRNA.…”

Section: Introductionmentioning

confidence: 99%

Prediction of response to treatment of chronic hepatitis B with pegylated interferon in the Philippines

Agdamag¹,

Kageyama²,

Leano³

et al. 2009

Journal of Medical Virology

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The response marker for interferon has not been investigated fully for hepatitis B viruses (HBVs) in the Philippines where novel subtypes B5 and C5 were recognized recently. The prediction parameters for interferon treatment were assessed, with emphasis on the mutation patterns in the basal core promoter and precore regions in patients with chronic hepatitis B. Seventeen HBeAg-positive patients were stratified according to response to treatment with pegylated interferon based on HBe seroconversion and HBV load. Intra-patient distributions of wild-type strains (A1762, G1764) and variants (T1762, A1764) were analyzed using HBV-DNA amplification and subsequent molecular cloning. The rate of variants (T1762, A1764) harbored by a patient was higher among responders (41.2% and 31% per person on average) than among non-responders (2.4% and 2.4%) to treatment with pegylated interferon at the baseline, respectively (P < 0.05). The rate of variants (T1762, A1764) harbored by responders (41.2% and 31%) decreased to 1.7% and 1.7%, and wild-type strains (A1762, G1764) conversely became majority (98.3% and 98.3%) after treatment with pegylated interferon, respectively. HBV strains harbored by two of six responders and a patient with lower baseline load (1.0 x 10(4) copies/ml) showed genotype shift from A to other genotypes, where genotype A disappeared preferentially after the loss of HBeAg and genotypes B and C formed a major population. These results suggest that the HBV variants (T1762, A1764) and HBV genotype A in the Philippines have an advantage in the response to pegylated interferon. These results warrant a large-scale examination for further precise prediction of the response to treatment with interferon.

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“…A83 mutation in the HBV precore region, 1762-1764 double mutation and deletions in the core promoter region could enhance viral replication [Chen and Oon, 2000]. This could result in an inability to synthesize hepatitis B e antigen (HBeAg) [Marrone et al, 2003;Tacke et al, 2004] and increase the risk of hepatocellular carcinoma in hepatitis B carriers [Kao et al, 2003]. The mutations in 'a' determinant epitope of HBsAg may result in a vaccine escape mutation [Shizuma et al, 2003].…”

Section: Introductionmentioning

confidence: 99%

Heterogeneity analysis of the hepatitis B virus genome in intrauterine infection

et al. 2005

J. Med. Virol.

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There are many factors leading to intrauterine infection with hepatitis B virus (HBV). These factors include viral structure, HBV mutations, HBV DNA level, placenta barrier, immune status of the mother, and susceptibility of the fetus. The purpose of this study was to investigate the possible relationship between intrauterine infection with and HBV mutations of the genome of the virus. In this study, HBsAg-positive mothers were divided into two groups: intrauterine infection group and non-infection group according to whether the newborn infants were infected or not. The intrauterine infection group included four pairs of mother and their newborn infants infected in utero, and non-infection group included five HBsAg-positive mothers. HBV sequences from the two groups were analyzed and compared. The predominant strains in the mothers and infants from the intrauterine infection group were not completely consistent. This suggested that both HBV predominant strains and minority strains in the mothers could infect their infants through intrauterine transmission. Some HBV mutations probably related to intrauterine infection were examined and it was found that the frequencies of mutations were low in isolates of the virus of infants from the intrauterine infection group and high in the non-infection group. These results suggest that some strains of HBV from the mother may be transmitted selectively to the fetus in utero because of viral heterogeneity. The strains without screened mutations such as P21L in the pre-S1 region may infect the fetus more readily.

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Low HBeAg Serum Levels Correlate with the Presence of the Double A1762T/G1764A Core Promoter Mutation and a Positive Response to Interferon in Patients with Chronic Hepatitis B Virus Infection

Cited by 15 publications

References 26 publications

Three‐phase sequential combined treatment with lamivudine and interferon in young patients with chronic hepatitis B

Three‐phase sequential combined treatment with lamivudine and interferon in young patients with chronic hepatitis B

Prediction of response to treatment of chronic hepatitis B with pegylated interferon in the Philippines

Heterogeneity analysis of the hepatitis B virus genome in intrauterine infection

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