New viral biomarkers for Hepatitis B: Are we able to change practice?

Siederdissen, Christoph Höner zu; Maasoumy, Benjamin; Cornberg, Markus

doi:10.1111/jvh.12993

Cited by 22 publications

(14 citation statements)

References 87 publications

(219 reference statements)

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“…Additional viral markers that may help to stratify patients or monitor the success of novel therapies are emerging but require further evaluation in larger studies. Quantitative hepatitis B core antibody (anti‐HBc) might be a useful marker of HBV‐induced liver disease and might help to discriminate phases of chronic HBV infection and to predict sustained response to antivirals, as well as risk of HBV reactivation in HBsAg‐negative patients .…”

Section: Endpoint Definitions For Hbv Therapy and Surrogates For Hbv mentioning

confidence: 99%

Guidance for Design and Endpoints of Clinical Trials in Chronic Hepatitis B—Report From the 2019 EASL‐AASLD HBV Treatment Endpoints Conference

et al. 2020

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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 hepatitis B virus (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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Section: Endpoint Definitions For Hbv Therapy and Surrogates For Hbv mentioning

confidence: 99%

Guidance for Design and Endpoints of Clinical Trials in Chronic Hepatitis B—Report From the 2019 EASL‐AASLD HBV Treatment Endpoints Conference

et al. 2020

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“…to predict virological relapse (VR) are HBV RNA or hepatitis B core antigen (HBcAg), which may be better surrogates of transcriptional covalently closed circular DNA. (14,15) A recent study has shown that detectable HBV RNA and HBcAg were associated with severe ALT flares after NA withdrawal. (16) So far, no host marker has been considered as a biomarker to predict the outcome after stopping NA therapy.…”

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confidence: 99%

Pilot Study Using Machine Learning to Identify Immune Profiles for the Prediction of Early Virological Relapse After Stopping Nucleos(t)ide Analogues in HBeAg-Negative CHB

Wübbolding

Alfonso

Lin

et al. 2021

Hepatology Communications

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Treatment with nucleos(t)ide analogues (NAs) may be stopped after 1-3 years of hepatitis B virus DNA suppression in hepatitis B e antigen (HBeAg)-negative patients according to Asian Pacific Association for the Study of Liver and European Association for the Study of Liver guidelines. However, virological relapse (VR) occurs in most patients. We aimed to analyze soluble immune markers (SIMs) and use machine learning to identify SIM combinations as predictor for early VR after NA discontinuation. A validation cohort was used to verify the predictive power of the SIM combination. In a post hoc analysis of a prospective, multicenter therapeutic vaccination trial (ABX-203, NCT02249988), hepatitis B surface antigen, hepatitis B core antigen, and 47 SIMs were repeatedly determined before NA was stopped. Forty-three HBeAg-negative patients were included. To detect the highest predictive constellation of host and viral markers, a supervised machine learning approach was used. Data were validated in a different cohort of 49 patients treated with entecavir. VR (hepatitis B virus DNA ≥ 2,000 IU/mL) occurred in 27 patients. The predictive value for VR of single SIMs at the time of NA stop was best for interleukin (IL)-2, IL-17, and regulated on activation, normal T cell expressed and secreted (RANTES/CCL5) with a maximum area under the curve of 0.65. Hepatitis B core antigen had a higher predictive power than hepatitis B surface antigen but lower than the SIMs. A supervised machinelearning algorithm allowed a remarkable improvement of early relapse prediction in patients treated with entecavir. The combination of IL-2, monokine induced by interferon γ (MIG)/chemokine (C-C motif) ligand 9 (CCL9), RANTES/ CCL5, stem cell factor (SCF), and TNF-related apoptosis-inducing ligand (TRAIL) was reliable in predicting VR (0.89; 95% confidence interval: 0.5-1.0) and showed viable results in the validation cohort (0.63; 0.1-0.99). Host immune markers such as SIMs appear to be underestimated in guiding treatment cessation in HBeAg-negative patients. Machine learning can help find predictive SIM patterns that allow a precise identification of patients particularly suitable for NA cessation. (Hepatology Communications 2020;0:1-15). C hronic hepatitis B is a major challenging health problem, with 250 million chronically infected patients worldwide. (1) Treatment options are either pegylated interferon alfa (PEG-IFN) or nucleoside or nucleotide analogues (NAs). (2) PEG-IFN has the advantage of finite treatment duration, but it has to be administered subcutaneously and side effects restrict its use. (2) Oral NAs are safe and highly effective in terms of hepatitis B virus (HBV) DNA suppression, but treatment duration is not finite.

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“…Serum HBsAg upon treatment at week 12 combined with HBV genotype has been shown to be associated with HBeAg seroconversion at 6 months post‐treatment, and this HBsAg‐based stopping rule is included later in 2017 EASL guidelines . Recently, some new on‐treatment predictors like hepatitis B core‐related antigen (HBcrAg) and HBV RNA have been studied on the PEG‐IFN treatment response (review by Ref …”

Section: Discussionmentioning

confidence: 99%

“…26 Recently, some new on-treatment predictors like hepatitis B core-related antigen (HBcrAg) and HBV RNA have been studied on the PEG-IFN treatment response (review by Ref. 44 ); however, further study is required to validate the clinical impact of these markers.…”

Section: Discussionmentioning

confidence: 99%

Elevated serum levels of soluble CD14 in HBeAg‐positive chronic HBV patients upon Peginterferon treatment are associated with treatment response

Dou

Montfoort

Bosch

et al. 2019

Journal of Viral Hepatitis

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Pegylated IFNα (PEG‐IFN) is one of the treatment options for chronic HBV (CHB) patients. However, the high patient treatment burden and limited response rate together clearly ask for biomarkers to predict PEG‐IFN response. Soluble CD14 (sCD14) is considered a marker for immune activation and has been shown to predict clinical outcome of HIV infection. However, studies on sCD14 in CHB infection are inconclusive, and its relationship with clinical outcome is largely unknown. Here, we measured sCD14 levels in CHB patients and investigated whether changes in sCD14 level related to PEG‐IFN response. Serum sCD14 levels were determined in 15 healthy controls, 15 acute self‐limited HBV, 60 CHB patients in different disease phases and 94 HBeAg+ CHB patients at week 0 and week 12 of a 52‐week PEG‐IFN treatment. Response to PEG‐IFN treatment was defined as HBeAg seroconversion or HBeAg loss at 26 weeks post‐treatment. The mean sCD14 level in acute HBV patients (3.0 µg/mL) was significantly higher than in CHB patients (2.4 µg/mL) and healthy controls (2.4 µg/mL). In CHB patients receiving PEG‐IFN, a significant increase in sCD14 was found after 12‐week treatment (median week 0:2.1 µg/mL; week 12:3.7 µg/mL). After 12‐week treatment, the fold change (FC = w12/w0) in sCD14 was significantly higher in responders compared to nonresponders (HBeAg seroconversion: median FCresponder = 2.1 vs FCnonresponder = 1.6; HBeAg loss: median FCresponder = 2.2 vs FCnonresponder = 1.5). Receiver operating characteristic curves demonstrated that FC‐sCD14wk12/wk0 levels can be of significant value as a stopping rule to select patients at week 12 who are not likely to benefit from further PEG‐IFN treatment.

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New viral biomarkers for Hepatitis B: Are we able to change practice?

Cited by 22 publications

References 87 publications

Guidance for Design and Endpoints of Clinical Trials in Chronic Hepatitis B—Report From the 2019 EASL‐AASLD HBV Treatment Endpoints Conference

Guidance for Design and Endpoints of Clinical Trials in Chronic Hepatitis B—Report From the 2019 EASL‐AASLD HBV Treatment Endpoints Conference

Pilot Study Using Machine Learning to Identify Immune Profiles for the Prediction of Early Virological Relapse After Stopping Nucleos(t)ide Analogues in HBeAg-Negative CHB

Elevated serum levels of soluble CD14 in HBeAg‐positive chronic HBV patients upon Peginterferon treatment are associated with treatment response

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