Reply to: “Ultrasensitive HBsAg testing predicts HBsAg seroreversion outcomes: Considerations for new and existing therapies”
Authors: Marc G. Ghany, Maria Buti, Pietro Lampertico, Hannah M. Lee
Journal: Journal of Hepatology (2024)

Guidance on treatment endpoints and study design for clinical trials aiming to achieve cure in chronic hepatitis B and D: Report from the 2022 AASLD-EASL HBV-HDV Treatment Endpoints ConferenceJournal of HepatologyVol. 79Issue 5PreviewRepresentatives from academia, industry, regulatory agencies, and patient advocacy groups convened under the American Association for the Study of Liver Diseases (AASLD) and the European Association for the Study of the Liver (EASL) in June 2022 with the primary goal of achieving consensus on chronic HBV and HDV treatment endpoints to guide clinical trials aiming to "cure" HBV and HDV. Conference participants reached an agreement on some key points. The preferred primary endpoint for phase II/III trials evaluating finite treatments for chronic hepatitis B (CHB) is a "functional" cure, defined as sustained HBsAg loss and HBV DNA less than the lower limit of quantitation (LLOQ) 24 weeks off-treatment. Full-Text PDF Ultrasensitive HBsAg testing predicts HBsAg seroreversion outcomes: Considerations for new and existing therapiesJournal of HepatologyPreviewWe recently read the AASLD and EASL 2022 HBV/HDV treatment endpoints and study design conference consensus statement with great interest.1 AASLD and EASL recommended "functional cure" as the primary endpoint for new HBV therapeutics under development, defined as HBsAg loss (S-loss) using a conventional HBsAg assay (limit of detection 0.05 IU/ml) and HBV DNA below the lower limit of quantification (<10 IU/ml) at 24 weeks off-therapy.1 Currently, predicting whether patients with therapy-driven S-loss will undergo HBsAg seroreversion or maintain S-loss after therapy is discontinued is difficult. Full-Text PDF Ultrasensitive HBsAg assays – not yet ready for primetime We thank the Journal for the opportunity to respond to an analysis to predict and define functional cure in chronic hepatitis B using a more sensitive quantitative hepatitis B surface antigen (qHBsAg) assay.1Anderson M. Holzmayer V. Stec M. et al.Ultrasensitive HBsAg testing predicts HBsAg seroreversion outcomes: considerations for new and existing therapies.J Hepatol. 2023 Nov 28; Google Scholar We agree with the authors that predicting durability of spontaneous or treatment-related HBsAg loss is an important issue and can be challenging. Several retrospective studies, using a HBsAg assay with a cut-off of 0.05 IU/ml to define HBsAg loss, have demonstrated that spontaneous or treatment-related HBsAg loss after confirmation (a minimum of two consecutive HBsAg negative results 3 to 6 months apart) is durable, ranging from 81% to 95% over 2 to 9.6 years follow-up.2Alawad A.S. Auh S. Suarez D. et al.Durability of spontaneous and treatment-related loss of hepatitis B s antigen.Clin Gastroenterol Hepatol. Mar 2020; 18: 700-709 e3https://doi.org/10.1016/j.cgh.2019.07.018Google Scholar, 3Lok A.S. Zoulim F. Dusheiko G. et al.Durability of hepatitis B surface antigen loss with nucleotide analogue and peginterferon therapy in patients with chronic hepatitis B.Hepatol Commun. Jan 2020; 4: 8-20https://doi.org/10.1002/hep4.1436Google Scholar, 4Yip T.C. Wong G.L. Wong V.W. et al.Durability of hepatitis B surface antigen seroclearance in untreated and nucleos(t)ide analogue-treated patients.J Hepatol. Oct 6 2017; https://doi.org/10.1016/j.jhep.2017.09.018Google Scholar Rates of HBsAg seroreversion were <10%2Alawad A.S. Auh S. Suarez D. et al.Durability of spontaneous and treatment-related loss of hepatitis B s antigen.Clin Gastroenterol Hepatol. Mar 2020; 18: 700-709 e3https://doi.org/10.1016/j.cgh.2019.07.018Google Scholar,4Yip T.C. Wong G.L. Wong V.W. et al.Durability of hepatitis B surface antigen seroclearance in untreated and nucleos(t)ide analogue-treated patients.J Hepatol. Oct 6 2017; https://doi.org/10.1016/j.jhep.2017.09.018Google Scholar with the exception of one study reporting a rate of 18%.3Lok A.S. Zoulim F. Dusheiko G. et al.Durability of hepatitis B surface antigen loss with nucleotide analogue and peginterferon therapy in patients with chronic hepatitis B.Hepatol Commun. Jan 2020; 4: 8-20https://doi.org/10.1002/hep4.1436Google Scholar After withdrawal of treatment, anti-HBs was detectable in 78% and 81% of people, after a median of 96 weeks and a mean of 9.6 years of follow up, respectively.3Lok A.S. Zoulim F. Dusheiko G. et al.Durability of hepatitis B surface antigen loss with nucleotide analogue and peginterferon therapy in patients with chronic hepatitis B.Hepatol Commun. Jan 2020; 4: 8-20https://doi.org/10.1002/hep4.1436Google Scholar,5Ghany M.G. Buti M. Lampertico P. et al.Faculty A-EH-HTEC. Guidance on treatment endpoints and study design for clinical trials aiming to achieve cure in chronic hepatitis B and D: report from the 2022 AASLD-EASL HBV-HDV Treatment Endpoints Conference.J Hepatol. Nov 2023; 79: 1254-1269https://doi.org/10.1016/j.jhep.2023.06.002Google Scholar Notably the presence of anti-HBs during or after HBsAg loss was not a factor associated with HBsAg seroreversion. The authors demonstrate that an ultrasensitive assay with a limit of detection of 0.005 IU/ml was better able to predict early HBsAg seroreversion within 24 weeks of stopping nucleos(t)ide analogue/peginterferon therapy among patients who cleared HBsAg on treatment – 10/11 (90.9%) patients who were reactive by the HBsAg Next assay experienced HBsAg seroreversion compared to only 1/20 (5%) who was negative by the HBsAg Next assay.1Anderson M. Holzmayer V. Stec M. et al.Ultrasensitive HBsAg testing predicts HBsAg seroreversion outcomes: considerations for new and existing therapies.J Hepatol. 2023 Nov 28; Google Scholar Although an additional two patients experienced HBsAg seroreversion with longer follow-up. In most studies analyzing durability of HBsAg loss, there is a requirement for HBsAg loss to be confirmed for some period of time, typically 24 weeks. Thus, patients with early HBsAg seroreversion, i.e. within the initial 24 weeks of follow-up are excluded, which may account for the high rate of HBsAg seroreversion of 30.5% in this report.1Anderson M. Holzmayer V. Stec M. et al.Ultrasensitive HBsAg testing predicts HBsAg seroreversion outcomes: considerations for new and existing therapies.J Hepatol. 2023 Nov 28; Google Scholar It would be of interest to repeat the analysis only including patients with confirmed HBsAg loss. Another important factor that likely affects the durability of HBsAg loss is the period of antiviral consolidation therapy following HBsAg loss. In one study of patients with confirmed HBsAg loss related to an interferon-based regimen, a period of consolidation therapy of 12-24 weeks compared to <12 weeks was associated with a lower rate of HBsAg seroreversion, 3.9% vs. 8.2%, respectively.6Li M. Sun F. Bi X. et al.Consolidation treatment needed for sustained HBsAg-negative response induced by interferon-alpha in HBeAg positive chronic hepatitis B patients.Virol Sin. Jun 2022; 37: 390-397https://doi.org/10.1016/j.virs.2022.03.001Google Scholar Thus, patients with HBsAg loss, who receive a longer period of antiviral therapy before treatment is stopped, may have more durable off-treatment HBsAg loss. Finally, with new drugs with different mechanisms of action, particularly those that affect translation of the HBsAg protein, HBsAg loss may be transient unless accompanied by immune control and development of anti-HBs. Further studies should explore if novel theapies that exclusively target viral replication may require a longer period of consolidation after HBsAg loss compared to immunomodulatory ones. We fully support studies that explore the use of more sensitive assays to investigate prediction and durability of HBsAg loss. Such studies may provide critical information on whether HBsAg levels lower than 0.05 IU/ml are indeed required for durable HBsAg loss, on the duration of consolidation therapy that may be needed to ensure durable off-treatment HBsAg loss with newer agents and if in fact the definition of functional cure should be revised. Until such time, we support the current definition of functional cure defined as HBsAg loss using a conventional HBsAg assay (limit of detection 0.05 IU/ml) and HBV DNA below the lower limit of quantification (<10 IU/ml) at 24 weeks off-therapy.5Ghany M.G. Buti M. Lampertico P. et al.Faculty A-EH-HTEC. Guidance on treatment endpoints and study design for clinical trials aiming to achieve cure in chronic hepatitis B and D: report from the 2022 AASLD-EASL HBV-HDV Treatment Endpoints Conference.J Hepatol. Nov 2023; 79: 1254-1269https://doi.org/10.1016/j.jhep.2023.06.002Google Scholar This work was supported by the Intramural Program of the National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health. The authors of this study declare that they do not have any conflict of interest. Please refer to the accompanying ICMJE disclosure forms for further details. All authors contributed to drafting and critical revision of the manuscript for important intellectual content. All authors are responsible for the content of the work. The following are the supplementary data to this article: Download .pdf (.59 MB) Help with pdf files Multimedia component 1