Impact of <scp>HBV</scp> genotype and mutations on <scp>HBV DNA</scp> and <scp>qHBsA</scp>g levels in patients with <scp>HB</scp>eAg‐negative chronic <scp>HBV</scp> infection

Kuhnhenn, Lisa; Jiang, Bin; Kubesch, Alica; Vermehren, Johannes; Knop, Viola; Susser, S.; Dietz, Julia; Carra, Gert; Finkelmeier, Fabian; Grammatikos, Georgios; Zeuzem, Stefan; Sarrazin, Christoph; Hildt, Eberhard; Peiffer, Kai‐Henrik

doi:10.1111/apt.14636

Cited by 37 publications

(40 citation statements)

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“…Based on the analysis of a large European cohort of HBV chronically infected patients, we identified an HBV genotype A mutant with a deletion of 15 aa (aa 25‐39 in the N‐terminal PreS1 domain . Western blot analysis of the serum of the patient using HBsAg‐specific antibodies did not show truncated LHBs, presumably due to the transcomplementation from integrated HBV‐DNA .…”

Section: Discussionmentioning

confidence: 99%

“…However, there are only few reports about the impact of N-terminal deletion in PreS1 on intracellular HBsAg localisation, HBsAg secretion and virus assembly. As the PreS1 exerts a variety of different functions in the viral life cycle, it is very crucial to investigate in detail how mutations in this part affect the virus life cycle.Based on the analysis of a large European cohort of HBV chronically infected patients, we identified an HBV genotype A mutant with a deletion of 15 aa (aa 25-39 in the N-terminal PreS1 domain 46,47. Western blot analysis of the serum of the patient using…”

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confidence: 99%

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Formation of semi‐enveloped particles as a unique feature of a hepatitis B virus PreS1 deletion mutant

Jiang

Kuhnhenn

et al. 2019

Aliment Pharmacol Ther

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Summary Background Naturally occurring variants with deletions or mutations in the C‐terminal PreS1 domain from hepatitis B virus (HBV) chronically infected patients have been shown to promote HBsAg retention, inhibit HBsAg secretion and change the extracellular appearance of PreS1‐containing HBV particles (filaments and virions). Aims To study the impact of N‐terminal deletion in preS1 domain on viral secretion and morphogenesis. Methods An HBV mutant with 15 amino acids (aa 25‐39) deletion in N‐terminal preS1 was isolated. Intracellular and extracellular HBsAg were quantified by Western blot. Subcellular HBsAg distribution was analysed by confocal laser scanning microscopy. The viral morphology was characterised by sucrose density gradient ultracentrifugation, Western blot, electron microscopy, HBV mixed ELISA and HBV particle gel essay. Results Expression of this mutant genome released higher amounts of HBsAg in the form of shorter filaments. A significant fraction of semi‐enveloped virions was observed in the supernatant that has been unprecedented so far. Stepwise insertion of aa 25‐31, aa 32‐39 and aa 25‐39 increased the length of filaments. The rescue of aa 25‐31 and aa 25‐39 drastically reduced the amounts of extracellular HBsAg and semi‐enveloped virions, while such effects could not be observed after insertion of aa 32‐39, arguing against a simple spacer function of this region. The deletion and rescued mutants do not differ in subcellular HBsAg distribution and colocalisation with ER, Golgi and multivesicular bodies markers arguing against differences in release pathways. Conclusion N‐terminal PreS1‐domain (aa 25‐31) determines HBsAg secretion and triggers proper assembly of PreS1‐containing particles.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Formation of semi‐enveloped particles as a unique feature of a hepatitis B virus PreS1 deletion mutant

Jiang

Kuhnhenn

et al. 2019

Aliment Pharmacol Ther

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“…23 The ability of HBsAg decline to predict HBsAg loss may be affected by HBeAg status, HBV genotype, and the type/target of the treatment used. 23,25 Therefore, a decline in HBsAg levels in phase II clinical trials should currently only be considered as an exploratory and not a surrogate endpoint. A decline of HBsAg as a surrogate marker in phase III trials can only be accepted if it is demonstrated (i.e.…”

Section: Nomenclaturementioning

confidence: 99%

Guidance for design and endpoints of clinical trials in chronic hepatitis B - Report from the 2019 EASL-AASLD HBV Treatment Endpoints Conference‡

Cornberg

Lok

Terrault

et al. 2020

Journal of Hepatology

243

122

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Representatives from academia, industry, regulatory agencies, and patient groups convened in March 2019 with the primary goal of developing agreement on chronic HBV treatment endpoints to guide clinical trials aiming to 'cure' HBV. Agreement among the conference participants was reached on some key points. 'Functional' but not sterilising cure is achievable and should be defined as sustained HBsAg loss in addition to undetectable HBV DNA 6 months post-treatment. The primary endpoint of phase III trials should be functional cure; HBsAg loss in > − 30% of patients was suggested as an acceptable rate of response in these trials. Sustained virologic suppression (undetectable serum HBV DNA) without HBsAg loss 6 months after discontinuation of treatment would be an intermediate goal. Demonstrated validity for the prediction of sustained HBsAg loss was considered the most appropriate criterion for the approval of new HBV assays to determine efficacy endpoints. Clinical trials aimed at HBV functional cure should initially focus on patients with HBeAg-positive or negative chronic hepatitis, who are treatment-naïve or virally suppressed on nucleos(t)ide analogues. A hepatitis flare associated with an increase in bilirubin or international normalised ratio should prompt temporary or permanent cessation of an investigational treatment. New treatments must be as safe as existing nucleos(t)ide analogues. The primary endpoint for phase III trials for HDV coinfection should be undetectable serum HDV RNA 6 months after stopping treatment. On treatment HDV RNA suppression associated with normalisation of alanine aminotransferase is considered an intermediate goal. In conclusion, regarding HBV 'functional cure', the primary goal is sustained HBsAg loss with undetectable HBV DNA after completion of treatment and the intermediate goal is sustained undetectable HBV DNA without HBsAg loss after stopping treatment.

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“…In their Editorial Alexopoulou and Karayiannis comment on our findings of the impact of the HBV genotype and frequent mutations on HBV DNA and qHBsAg levels in HBeAg‐negative chronic HBV‐infected patients . The authors of the Editorial point out that our data about qHBsAg levels might be of clinical relevance, as the qHBsAg seems not to be accurate enough in identifying inactive carriers, irrespective of their HBV genotype. Indeed, in our study qHBsAg levels vary significantly up to 1.4 log among the HBV genotypes A‐E.…”

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confidence: 91%

Editorial: HBsAg serum levels in HBeAg‐negative chronic HBV infection—is it a matter of genotype? Authors’ reply

Kuhnhenn

Jiang

Kubesch

et al. 2018

Aliment Pharmacol Ther

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Impact of HBV genotype and mutations on HBV DNA and qHBsAg levels in patients with HBeAg‐negative chronic HBV infection

Abstract: qHBsAg serum levels depend on the HBV genotype and together with HBV DNA levels on frequent mutations in PC, BCP and preS in HBeAg-negative patients. qHBsAg cut-offs when used as prognostic markers require genotype-dependent validation.

Cited by 37 publications

References 35 publications

Formation of semi‐enveloped particles as a unique feature of a hepatitis B virus PreS1 deletion mutant

Formation of semi‐enveloped particles as a unique feature of a hepatitis B virus PreS1 deletion mutant

Guidance for design and endpoints of clinical trials in chronic hepatitis B - Report from the 2019 EASL-AASLD HBV Treatment Endpoints Conference‡

Editorial: HBsAg serum levels in HBeAg‐negative chronic HBV infection—is it a matter of genotype? Authors’ reply

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