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Conference Paper: Utility of a new HBV RNA assay in HBeAg positive and negative CHB and following HBsAg seroclearance in patients treated with ARC‐520, an RNAi drug targeting cccDNA derived HBV mRNA

TitleUtility of a new HBV RNA assay in HBeAg positive and negative CHB and following HBsAg seroclearance in patients treated with ARC‐520, an RNAi drug targeting cccDNA derived HBV mRNA
Authors
Issue Date2018
PublisherWiley-Blackwell Publishing Ltd. The Journal's web site is located at http://onlinelibrary.wiley.com/journal/10.1111/(ISSN)1365-2893
Citation
The 16th International Symposium on Viral Hepatitis and Liver Diseases (ISVHLD), Toronto, Canada, 14-17 June 2018, In Journal of Viral Hepatitis, 2018, v. 25 n. S2, p. 190-191, abstract no. LBO‐02 How to Cite?
AbstractBackground: ARC‐520 Injection (ARC), a RNA interference drug, targets cccDNA‐derived mRNA in chronic hepatitis B patients (CHB). We previously reported that HBsAg reductions were larger in naïve HBeAg‐pos CHB compared to naïve HBeAg‐neg CHB, attributed to higher expression of HBsAg from integrated HBV DNA in HBeAg‐neg. Here we report on the effect of ARC on serum HBV RNA using a new assay in conjunction with other HBV markers. Methods: 8 treatment naïve CHB (5 HBeAg‐neg, 3 HBeAg‐pos) received up to 9 doses of 4 mg/kg ARC once every 4 weeks with daily entecavir (ETV). Viral DNA, RNA and antigen knockdown were measured [qHBsAg, HB core‐related antigen (qHBcrAg) in all, qHBeAg in HBeAg‐pos]. Serum HBV RNA was quantitated using a high‐throughput assay on the Abbott m2000 system with a limit of quantitation of 45 U/mL (where 1 U of HBV RNA = 1 IU HBV DNA) and by the Van Boemmel method (Hepatology, 2015). Results: The Abbott HBV RNA assay showed good selectivity. After initiation of ETV plus ARC, HBV RNA showed no correlation with rapidly decreasing HBV DNA. A good correlation with the Van Boemmel assay was seen above the LLOQ (r2=0.88) but the new test had increased sensitivity. In HBeAg‐pos, HBV RNA correlated well with qHBsAg (r2=0.86), qHBeAg (r2=0.85), and qHBcrAg (r2=0.90), all of which showed large reductions during therapy and follow‐up. This was the case regardless of whether antigen reductions were observed in direct response to ARC or off‐therapy, possibly due to sustained host virologic control. In HBeAg‐neg CHB, no correlation between measurable qHBsAg or qHBcrAg and HBV RNA was observed, despite one CHB achieving HBsAg seroclearance. No viral products were detectable in this patient post seroclearance. Conclusions: (1) The Abbott HBV RNA assay showed good selectivity for HBV RNA, higher sensitivity and a good correlation with the Van Boemmel assay. (2) In HBeAg‐pos CHB, HBV RNA correlated well with quantitative serum antigens, consistent with the mode of action of ARC. (3) In HBeAg‐neg CHB, no correlation of HBV RNA with serum antigens was observed. Possible reasons could be differences in sensitivity between the assays, design of the HBV RNA assay, or a disproportionate effect of ARC on HBcrAg, which is exclusively derived from cccDNA, while not affecting total mRNA levels in HBeAg‐neg CHB. 4) Studies with the novel RNAi therapy ARO‐HBV, designed to suppress viral RNA from all sources could further elucidate the role of serum markers in CHB management. References: Van Bommel, F., Bartens A, Mysickova A, Hofmann J, Krüger DH, Berg T, Edelmann A. Serum hepatitis B virus RNA levels as an early predictor of hepatitis B envelope antigen seroconversion during treatment with polymerase inhibitors. Hepatology. 2015 Jan;61(1):66–76.
Persistent Identifierhttp://hdl.handle.net/10722/263570
ISSN
2017 Impact Factor: 4.237
2015 SCImago Journal Rankings: 1.815

 

DC FieldValueLanguage
dc.contributor.authorButer, EK-
dc.contributor.authorWong, DKH-
dc.contributor.authorJackson, K-
dc.contributor.authorSchluep, T-
dc.contributor.authorGersch, J-
dc.contributor.authorKuhns, M-
dc.contributor.authorCloherty, GA-
dc.contributor.authorLocarnini, S-
dc.contributor.authorYuen, RMF-
dc.date.accessioned2018-10-22T07:41:04Z-
dc.date.available2018-10-22T07:41:04Z-
dc.date.issued2018-
dc.identifier.citationThe 16th International Symposium on Viral Hepatitis and Liver Diseases (ISVHLD), Toronto, Canada, 14-17 June 2018, In Journal of Viral Hepatitis, 2018, v. 25 n. S2, p. 190-191, abstract no. LBO‐02-
dc.identifier.issn1352-0504-
dc.identifier.urihttp://hdl.handle.net/10722/263570-
dc.description.abstractBackground: ARC‐520 Injection (ARC), a RNA interference drug, targets cccDNA‐derived mRNA in chronic hepatitis B patients (CHB). We previously reported that HBsAg reductions were larger in naïve HBeAg‐pos CHB compared to naïve HBeAg‐neg CHB, attributed to higher expression of HBsAg from integrated HBV DNA in HBeAg‐neg. Here we report on the effect of ARC on serum HBV RNA using a new assay in conjunction with other HBV markers. Methods: 8 treatment naïve CHB (5 HBeAg‐neg, 3 HBeAg‐pos) received up to 9 doses of 4 mg/kg ARC once every 4 weeks with daily entecavir (ETV). Viral DNA, RNA and antigen knockdown were measured [qHBsAg, HB core‐related antigen (qHBcrAg) in all, qHBeAg in HBeAg‐pos]. Serum HBV RNA was quantitated using a high‐throughput assay on the Abbott m2000 system with a limit of quantitation of 45 U/mL (where 1 U of HBV RNA = 1 IU HBV DNA) and by the Van Boemmel method (Hepatology, 2015). Results: The Abbott HBV RNA assay showed good selectivity. After initiation of ETV plus ARC, HBV RNA showed no correlation with rapidly decreasing HBV DNA. A good correlation with the Van Boemmel assay was seen above the LLOQ (r2=0.88) but the new test had increased sensitivity. In HBeAg‐pos, HBV RNA correlated well with qHBsAg (r2=0.86), qHBeAg (r2=0.85), and qHBcrAg (r2=0.90), all of which showed large reductions during therapy and follow‐up. This was the case regardless of whether antigen reductions were observed in direct response to ARC or off‐therapy, possibly due to sustained host virologic control. In HBeAg‐neg CHB, no correlation between measurable qHBsAg or qHBcrAg and HBV RNA was observed, despite one CHB achieving HBsAg seroclearance. No viral products were detectable in this patient post seroclearance. Conclusions: (1) The Abbott HBV RNA assay showed good selectivity for HBV RNA, higher sensitivity and a good correlation with the Van Boemmel assay. (2) In HBeAg‐pos CHB, HBV RNA correlated well with quantitative serum antigens, consistent with the mode of action of ARC. (3) In HBeAg‐neg CHB, no correlation of HBV RNA with serum antigens was observed. Possible reasons could be differences in sensitivity between the assays, design of the HBV RNA assay, or a disproportionate effect of ARC on HBcrAg, which is exclusively derived from cccDNA, while not affecting total mRNA levels in HBeAg‐neg CHB. 4) Studies with the novel RNAi therapy ARO‐HBV, designed to suppress viral RNA from all sources could further elucidate the role of serum markers in CHB management. References: Van Bommel, F., Bartens A, Mysickova A, Hofmann J, Krüger DH, Berg T, Edelmann A. Serum hepatitis B virus RNA levels as an early predictor of hepatitis B envelope antigen seroconversion during treatment with polymerase inhibitors. Hepatology. 2015 Jan;61(1):66–76.-
dc.languageeng-
dc.publisherWiley-Blackwell Publishing Ltd. The Journal's web site is located at http://onlinelibrary.wiley.com/journal/10.1111/(ISSN)1365-2893-
dc.relation.ispartofJournal of Viral Hepatitis-
dc.relation.ispartofThe 16th International Symposium on Viral Hepatitis and Liver Diseases (ISVHLD), 2018-
dc.titleUtility of a new HBV RNA assay in HBeAg positive and negative CHB and following HBsAg seroclearance in patients treated with ARC‐520, an RNAi drug targeting cccDNA derived HBV mRNA-
dc.typeConference_Paper-
dc.identifier.emailWong, DKH: danywong@hku.hk-
dc.identifier.emailYuen, RMF: mfyuen@hku.hk-
dc.identifier.authorityWong, DKH=rp00492-
dc.identifier.authorityYuen, RMF=rp00479-
dc.identifier.doi10.1111/jvh.01_12935-
dc.identifier.hkuros293815-
dc.identifier.volume25-
dc.identifier.issueS2-
dc.identifier.spage190-
dc.identifier.epage191-
dc.publisher.placeUnited Kingdom-

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