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Quantified integrated hepatitis B virus is related to viral activity in patients with chronic hepatitis B
Erken, R.; Loukachov, V.; Dort, K.; Hurk, A. den; Takkenberg, R.B.; Niet, A.; ... ; Kootstra, N. 2022
Quantified integrated hepatitis B virus is related to viral activity in patients with chronic hepatitis B
Article / Letter to editor
open access
Background and Aims: HBV can integrate in the host genome of the hepat-ocyte and recent findings suggest that integrated HBV contributes to the per-sistent production of viral proteins. Here, we... Show moreBackground and Aims: HBV can integrate in the host genome of the hepat-ocyte and recent findings suggest that integrated HBV contributes to the per-sistent production of viral proteins. Here, we quantified the levels of integratedHBV in patients with chronic hepatitis B (CHB) and analyzed the relation be-tween HBV integration, virological activity (plasma HBV DNA and HBsAg lev-els), and clinical outcomes.Approach and Results: We developed and validated a multistep Arthrobacterluteus (Alu)- PCR that specifically amplifies integrated HBV and RT-Alu- PCRdetecting mRNA transcripts derived from integrated HBV. Pretreatment liverbiopsy samples and baseline characteristics of 124 patients with CHB eithertreated for 48 weeks with pegylated interferon plus adefovir or tenofovir or re-ceiving no treatment were available for analysis. Integrated HBV sequencescontaining open reading frame S and X (but not C) and S and X mRNA tran-scripts derived from integrated HBV could be detected and quantified in liverbiopsies. Integrated HBV levels correlated with HBV DNA, HBsAg, alanineaminotransferase plasma levels, and the liver histology activity index but notto levels of intrahepatic covalently closed circular DNA (cccDNA), plasmapregenomic RNA, or hepatitis B core-related antigen. Multivariable logisticregression analysis showed that lower baseline HBV integration levels wereindependently associated with HBsAg loss (functional cure) within 5 yearsfollow-up.Conclusions: Integrated HBV levels are strongly correlated with surrogatemarkers for virological activity but not to cccDNA levels and are predictivefor HBsAg loss. Our data suggest that integrated HBV is closely related toHBV replication and may therefore be an important tool in the evaluation anddevelopment of treatment modalities aiming to cure CHB. Show less
Farnesoid X receptor agonist for the treatment of chronic hepatitis B
Erken, R.; Andre, P.; Roy, E.; Kootstra, N.; Barzic, N.; Girma, H.; ... ; Reesink, H. 2021
Farnesoid X receptor agonist for the treatment of chronic hepatitis B: a safety study
Article / Letter to editor
open access
The nuclear farnesoid X receptor (FXR) regulates bile acid homeostasis and is a drug target for metabolic liver diseases. FXR also plays an important role in hepatitis B virus (HBV) DNA... Show moreThe nuclear farnesoid X receptor (FXR) regulates bile acid homeostasis and is a drug target for metabolic liver diseases. FXR also plays an important role in hepatitis B virus (HBV) DNA transcription. In vitro and in mice, FXR agonist treatment leads to inhibition of viral replication and a decline in viral proteins, pregenomic RNA (pgRNA) and HBV DNA levels. We aimed to translate this to a clinical use by primarily evaluating the safety and secondary the anti-viral effect of Vonafexor, a FXR agonist, in chronic hepatitis B (CHB) patients. In total, 73 CHB patients were enrolled in a two-part Phase Ib double-blind, placebo-controlled trial. Patients were randomized to receive oral Vonafexor (100, 200 and 400 mg once daily, or 200 mg twice daily), placebo, or entecavir (Part A, n = 48) or to receive Vonafexor (300 mg once daily or 150 mg twice daily), or placebo, combined with pegylated-interferon-alpha 2a (Part B, n = 25) for 29 days. Patients were followed up for 35 days. Enrolled CHB patients were mostly HBeAg-negative. Vonafexor was overall well tolerated and safe. The most frequent adverse events were moderate gastrointestinal events. Pruritus was more frequent with twice-daily compared with once-daily regimens (56%-67% vs. 16%, respectively, p < 0.05). Vonafexor monotherapy of 400 mg once daily decreased HBsAg concentrations (-0.1 log(10) IU/mL, p < 0.05), and Vonafexor/pegylated-IFN-alpha 2a combination therapy decreased HBcrAg and pgRNA. In conclusion, Vonafexor was safe with a decline in HBV markers observed in CHB patients suggesting a potential anti-viral effect the therapeutic potential of which has to be evaluated in larger trials. Show less
Farnesoid X receptor agonist for the treatment of chronic hepatitis B: A safety study
Erken, R.; Andre, P.; Roy, E.; Kootstra, N.; Barzic, N.; Girma, H.; ... ; Reesink, H. 2021
Farnesoid X receptor agonist for the treatment of chronic hepatitis B: A safety study
Article / Letter to editor
metadata only
A prospective five-year follow-up after peg-interferon plus nucleotide analogue treatment or no treatment in HBeAg negative chronic hepatitis B patients
Erken, R.; Loukachov, V.V.; Niet, A. de; Jansen, L.; Stelma, F.; Helder, J.T.; ... ; Reesink, H.W. 2021
A prospective five-year follow-up after peg-interferon plus nucleotide analogue treatment or no treatment in HBeAg negative chronic hepatitis B patients
Article / Letter to editor
open access
Background: Currently available treatment options for chronic hepatitis B (CHB) are not recommended for HBeAg-negative patients with a low viral load. These patients may however benefit from... Show moreBackground: Currently available treatment options for chronic hepatitis B (CHB) are not recommended for HBeAg-negative patients with a low viral load. These patients may however benefit from treatment by achieving a functional cure, defined by HBsAg-loss and undetectable HBV DNA. This study evaluated the long-term effect of combination treatment with peg-interferon-alpha-2a (peg-IFN) and adefovir or tenofovir compared to no treatment in these patients. Methods: HBeAg-negative CHB patients with HBV-DNA levels < 20,000 IU/mL (n = 151) were previously randomised 1:1:1 for peg-IFN 180 mg/week plus either adefovir 10 mg/day or tenofovir 245 mg/day, or no treatment and treated for 48 weeks in an open-label study. In this prospective long-term follow-up study, patients were monitored yearly up to five years after end of treatment (week 308). The primary outcome was sustained HBsAg-loss and secondary outcome the dynamics of HBsAg and HBV-DNA levels over time. Results: Of the 131 followed patients, the HBsAg-status was known for 118 patients after five-year follow-up. HBsAg-loss occurred similarly (P = 0.703) in all arms: 8/43 (18.6%) peg-IFN + adefovir, 4/34 (11.7%) peg-IFN + tenofovir, and 6/41 (14.6%) among the untreated patients. The time to HBsAg-loss did not differ between groups (P = 0.641). Low baseline HBsAg levels and genotype A were independently associated with HBsAg-loss irrespective of allocation. HBsAg and HBV-DNA levels declined similarly during follow-up in all patient groups. Conclusions: This prospective randomised controlled study showed that HBsAg-loss overtime was not influenced by treatment with a combination of nucleotide analogue and Peg-IFN. Low baseline HBsAg levels can predict HBsAg-loss irrespective of treatment allocation. ( J CLIN EXP HEPATOL 2022;12:735–744) Show less
Hepatitis B core related antigen in relation to intrahepatic and circulating viral markers, before and after combination therapy
Erken, R.; Zaaijer, H.L.; Willemse, S.B.; Bakker, E.; Takkenberg, B.B.; Reesink, H.W.; Kootstra, N.A. 2021
Hepatitis B core related antigen in relation to intrahepatic and circulating viral markers, before and after combination therapy: an appraisal of lateral lymph nodes in rectal cancer
Article / Letter to editor
open access
Introduction and ObjectivesCovalently closed circular (ccc)DNA acts as a viral reservoir in the liver of patients with a chronic hepatitis B (CHB) infection and can only be quantified in liver... Show more

Introduction and ObjectivesCovalently closed circular (ccc)DNA acts as a viral reservoir in the liver of patients with a chronic hepatitis B (CHB) infection and can only be quantified in liver biopsies. Hepatitis B core-related antigen (HBcrAg) levels in plasma/serum have been proposed to reflect intrahepatic cccDNA-levels and may therefore monitor treatment efficacy. This study aimed to validate the relationship between HBcrAg and other intrahepatic and circulating viral markers in CHB patients with high viral load, before and after combination treatment.Materials and methodsPlasma/serum levels of HBcrAg, HBsAg, HBV-DNA, and HBV pregenomic RNA (HBV-pgRNA), and intrahepatic cccDNA and HBV-DNA levels and fibrosis scores were measured in 89 CHB patients with HBV-DNA levels of >100,000 copies/mL (17,182 IU/mL). Measurements were done before and after a 48-week treatment with pegylated interferon alfa-2a and adefovir in a prospective study (ISRCTN77073364).ResultsBaseline HBcrAg-values correlated strongly with intrahepatic cccDNA (ρ 0.77, p < 0.001), intrahepatic HBV-DNA (ρ 0.73, p < 0.001) and plasma/serum HBV-DNA (ρ 0.80, p < 0.001), HBV-pgRNA (ρ 0.80, p < 0.001), and to lesser extend HBsAg (ρ 0.56, p < 0.001). Baseline HBcrAg-levels could not predict functional cure (FC) but HBcrAg-levels declined more strongly in patients who developed FC or HBeAg-loss. Furthermore, most correlations persisted at the end of treatment and follow-up.ConclusionsHBcrAg reflects cccDNA transcription activity more accurately than HBsAg and may replace HBV-DNA as a marker during future treatment regimens, especially when cccDNA transcription is targeted or nucleot(s)ide analogues are included in the treatment regime.

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