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
Representatives from academia, industry, regulatory agencies, and patient advocacy groups convened under AASLD and EASL in June 2022 with the primary goal of achieving consensus on chronic hepatitis B virus (HBV) and hepatitis delta virus (HDV) (HDV) treatment endpoints to guide clinical trials aimi...
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| Veröffentlicht in: | Journal of hepatology 2023-11, Vol.79 (5), p.1254-1269 |
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| creator | Ghany, Marc G. Buti, Maria Lampertico, Pietro Lee, Hannah M. Berg, Thomas Brunetto, Maurizia R. Buchholz, Stephanie Buti, Maria Chang, Kyong-Mi Chen, Jacki Cornberg, Markus Dandri, Maura Dusheiko, Geoffrey Easterbrook, Philippa Feld, Jordan J. Ghany, Marc Janssen, Harry L.A. Korenjak, Marko Lampertico, Pietro Lee, Hannah Liang, Jake Lok, Anna S. Negro, Francesco Rehermann, Barbara Sheikh, Virginia Papatheodoridis, George Petersen, Jӧrg Terrault, Norah Younossi, Zobair M. Yuen, Man-Fung |
| description | Representatives from academia, industry, regulatory agencies, and patient advocacy groups convened under AASLD and EASL in June 2022 with the primary goal of achieving consensus on chronic hepatitis B virus (HBV) and hepatitis delta virus (HDV) (HDV) treatment endpoints to guide clinical trials aiming to “cure” HBV and HDV. Conference participants reached agreement on some key points. The preferred primary endpoint for phase II/III trials evaluating finite treatments for chronic hepatitis B (CHB) is “functional” cure, defined as sustained HBsAg loss and HBV DNA less than lower limit of quantification (LLOQ) 24 weeks off-treatment. An alternate endpoint would be “partial cure” defined as sustained HBsAg level |
| doi_str_mv | 10.1016/j.jhep.2023.06.002 |
| format | Article |
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Conference participants reached agreement on some key points. The preferred primary endpoint for phase II/III trials evaluating finite treatments for chronic hepatitis B (CHB) is “functional” cure, defined as sustained HBsAg loss and HBV DNA less than lower limit of quantification (LLOQ) 24 weeks off-treatment. An alternate endpoint would be “partial cure” defined as sustained HBsAg level <100 IU/mL and HBV DNA <LLOQ 24 weeks off-treatment. Clinical trials should initially focus on patients with HBeAg-positive or negative chronic hepatitis B, who are treatment-naїve or virally suppressed on nucleos(t)ide analogues. Hepatitis flares may occur during curative therapy and should be promptly investigated and outcomes reported. HBsAg loss would be the preferred endpoint for chronic hepatitis D, but HDV RNA <LLOQ 24 weeks off-treatment is a suitable alternate primary endpoint of phase II/III trials assessing finite strategies. For trials assessing maintenance therapy, the primary endpoint should be HDV RNA <LLOQ assessed at on-treatment week 48. An alternate endpoint would be ≥2 log reduction in HDV RNA combined with normalization of alanine aminotransferase (ALT) level. Suitable candidates for phase II/III trials would be treatment-naїve or -experienced patients with quantifiable HDV RNA. Novel biomarkers (HBcrAg, HBV RNA) remain exploratory while nucleos(t)ide analogues and pegylated interferon still have a role in combination with novel agents. Importantly, patient input is encouraged early on in drug development under the FDA/EMA patient-focused drug development programs.</description><identifier>ISSN: 0168-8278</identifier><identifier>ISSN: 1600-0641</identifier><identifier>EISSN: 1600-0641</identifier><identifier>DOI: 10.1016/j.jhep.2023.06.002</identifier><identifier>PMID: 37377088</identifier><language>eng</language><publisher>Netherlands: Elsevier B.V</publisher><subject>Antiviral Agents - therapeutic use ; Biomarkers ; Cirrhosis ; Clinical Outcomes ; Clinical Trials as Topic - methods ; Clinical Trials, Phase II as Topic - methods ; Cure ; DNA, Viral - analysis ; DNA, Viral - blood ; Endpoint Determination - methods ; Hepatitis B Surface Antigens - blood ; Hepatitis B virus - genetics ; Hepatitis B, Chronic - drug therapy ; Hepatitis B, Chronic - therapy ; Hepatitis B, Chronic - virology ; Hepatitis D, Chronic - drug therapy ; Hepatitis Delta Virus - genetics ; Humans ; Novel therapy ; Research Design ; Treatment Outcome</subject><ispartof>Journal of hepatology, 2023-11, Vol.79 (5), p.1254-1269</ispartof><rights>2023 European Association for the Study of the Liver, American Association for the Study of Liver Diseases</rights><rights>Copyright © 2023 European Association for the Study of the Liver, American Association for the Study of Liver Diseases. Published by Elsevier B.V. All rights reserved.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c3152-d118a5c33b4a1c00bf4b500bef30c5f4057a96e7c66d03b12add27aff248a553</citedby><cites>FETCH-LOGICAL-c3152-d118a5c33b4a1c00bf4b500bef30c5f4057a96e7c66d03b12add27aff248a553</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S0168827823004178$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,776,780,3537,27901,27902,65306</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/37377088$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Ghany, Marc G.</creatorcontrib><creatorcontrib>Buti, Maria</creatorcontrib><creatorcontrib>Lampertico, Pietro</creatorcontrib><creatorcontrib>Lee, Hannah M.</creatorcontrib><creatorcontrib>Berg, Thomas</creatorcontrib><creatorcontrib>Brunetto, Maurizia R.</creatorcontrib><creatorcontrib>Buchholz, Stephanie</creatorcontrib><creatorcontrib>Buti, Maria</creatorcontrib><creatorcontrib>Chang, Kyong-Mi</creatorcontrib><creatorcontrib>Chen, Jacki</creatorcontrib><creatorcontrib>Cornberg, Markus</creatorcontrib><creatorcontrib>Dandri, Maura</creatorcontrib><creatorcontrib>Dusheiko, Geoffrey</creatorcontrib><creatorcontrib>Easterbrook, Philippa</creatorcontrib><creatorcontrib>Feld, Jordan J.</creatorcontrib><creatorcontrib>Ghany, Marc</creatorcontrib><creatorcontrib>Janssen, Harry L.A.</creatorcontrib><creatorcontrib>Korenjak, Marko</creatorcontrib><creatorcontrib>Lampertico, Pietro</creatorcontrib><creatorcontrib>Lee, Hannah</creatorcontrib><creatorcontrib>Liang, Jake</creatorcontrib><creatorcontrib>Lok, Anna S.</creatorcontrib><creatorcontrib>Negro, Francesco</creatorcontrib><creatorcontrib>Rehermann, Barbara</creatorcontrib><creatorcontrib>Sheikh, Virginia</creatorcontrib><creatorcontrib>Papatheodoridis, George</creatorcontrib><creatorcontrib>Petersen, Jӧrg</creatorcontrib><creatorcontrib>Terrault, Norah</creatorcontrib><creatorcontrib>Younossi, Zobair M.</creatorcontrib><creatorcontrib>Yuen, Man-Fung</creatorcontrib><creatorcontrib>2022 AASLD-EASL HBV-HDV Treatment Endpoints Conference Faculty</creatorcontrib><title>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</title><title>Journal of hepatology</title><addtitle>J Hepatol</addtitle><description>Representatives from academia, industry, regulatory agencies, and patient advocacy groups convened under AASLD and EASL in June 2022 with the primary goal of achieving consensus on chronic hepatitis B virus (HBV) and hepatitis delta virus (HDV) (HDV) treatment endpoints to guide clinical trials aiming to “cure” HBV and HDV. Conference participants reached agreement on some key points. The preferred primary endpoint for phase II/III trials evaluating finite treatments for chronic hepatitis B (CHB) is “functional” cure, defined as sustained HBsAg loss and HBV DNA less than lower limit of quantification (LLOQ) 24 weeks off-treatment. An alternate endpoint would be “partial cure” defined as sustained HBsAg level <100 IU/mL and HBV DNA <LLOQ 24 weeks off-treatment. Clinical trials should initially focus on patients with HBeAg-positive or negative chronic hepatitis B, who are treatment-naїve or virally suppressed on nucleos(t)ide analogues. Hepatitis flares may occur during curative therapy and should be promptly investigated and outcomes reported. HBsAg loss would be the preferred endpoint for chronic hepatitis D, but HDV RNA <LLOQ 24 weeks off-treatment is a suitable alternate primary endpoint of phase II/III trials assessing finite strategies. For trials assessing maintenance therapy, the primary endpoint should be HDV RNA <LLOQ assessed at on-treatment week 48. An alternate endpoint would be ≥2 log reduction in HDV RNA combined with normalization of alanine aminotransferase (ALT) level. Suitable candidates for phase II/III trials would be treatment-naїve or -experienced patients with quantifiable HDV RNA. Novel biomarkers (HBcrAg, HBV RNA) remain exploratory while nucleos(t)ide analogues and pegylated interferon still have a role in combination with novel agents. Importantly, patient input is encouraged early on in drug development under the FDA/EMA patient-focused drug development programs.</description><subject>Antiviral Agents - therapeutic use</subject><subject>Biomarkers</subject><subject>Cirrhosis</subject><subject>Clinical Outcomes</subject><subject>Clinical Trials as Topic - methods</subject><subject>Clinical Trials, Phase II as Topic - methods</subject><subject>Cure</subject><subject>DNA, Viral - analysis</subject><subject>DNA, Viral - blood</subject><subject>Endpoint Determination - methods</subject><subject>Hepatitis B Surface Antigens - blood</subject><subject>Hepatitis B virus - genetics</subject><subject>Hepatitis B, Chronic - drug therapy</subject><subject>Hepatitis B, Chronic - therapy</subject><subject>Hepatitis B, Chronic - virology</subject><subject>Hepatitis D, Chronic - drug therapy</subject><subject>Hepatitis Delta Virus - genetics</subject><subject>Humans</subject><subject>Novel therapy</subject><subject>Research Design</subject><subject>Treatment Outcome</subject><issn>0168-8278</issn><issn>1600-0641</issn><issn>1600-0641</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2023</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kU9vEzEQxVcIREPhC3BAc-Sy27G9_4K4pE1pkCIhQdWr5dizjaOsHWxvpX67fjQcUjghLjOX33t6M68o3jOsGLL2YlfttnSoOHJRYVsh8hfFjLWIJbY1e1nMMtSXPe_6s-JNjDtEFDivXxdnohNdh30_K55uJmuU0wTeQQqk0kguATlz8NalCMoZiGkyj2Ao2nsHgw-g99ZZrfZZYdU-Q3a07h6SB6W3lh4I9BQIrAO9DT6jkIOqZJONcPnbcvkJvtPBhwRD8COkLUG-g8Ni8WO9LK_zhNXl3cVqeffPVNq7gQLl3G-LV0OOQO-e93lx--X69mpVrr_dfL1arEstWMNLw1ivGi3EplZMI26GetPkRYNA3Qw1Np2at9TptjUoNowrY3inhoHXWdeI8-LjyfYQ_M-JYpKjjZr2e-XIT1HyXmDbsTnDjPITqoOPMdAgD8GOKjxKhvJYnNzJY3HyWJzEVubisujDs_-0Gcn8lfxpKgOfTwDlIx8sBRm1PT7A2EA6SePt__x_AZ-FquU</recordid><startdate>20231101</startdate><enddate>20231101</enddate><creator>Ghany, Marc G.</creator><creator>Buti, Maria</creator><creator>Lampertico, Pietro</creator><creator>Lee, Hannah M.</creator><creator>Berg, Thomas</creator><creator>Brunetto, Maurizia R.</creator><creator>Buchholz, Stephanie</creator><creator>Buti, Maria</creator><creator>Chang, Kyong-Mi</creator><creator>Chen, Jacki</creator><creator>Cornberg, Markus</creator><creator>Dandri, Maura</creator><creator>Dusheiko, Geoffrey</creator><creator>Easterbrook, Philippa</creator><creator>Feld, Jordan J.</creator><creator>Ghany, Marc</creator><creator>Janssen, Harry L.A.</creator><creator>Korenjak, Marko</creator><creator>Lampertico, Pietro</creator><creator>Lee, Hannah</creator><creator>Liang, Jake</creator><creator>Lok, Anna S.</creator><creator>Negro, Francesco</creator><creator>Rehermann, Barbara</creator><creator>Sheikh, Virginia</creator><creator>Papatheodoridis, George</creator><creator>Petersen, Jӧrg</creator><creator>Terrault, Norah</creator><creator>Younossi, Zobair M.</creator><creator>Yuen, Man-Fung</creator><general>Elsevier B.V</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope></search><sort><creationdate>20231101</creationdate><title>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</title><author>Ghany, Marc G. ; Buti, Maria ; Lampertico, Pietro ; Lee, Hannah M. ; Berg, Thomas ; Brunetto, Maurizia R. ; Buchholz, Stephanie ; Buti, Maria ; Chang, Kyong-Mi ; Chen, Jacki ; Cornberg, Markus ; Dandri, Maura ; Dusheiko, Geoffrey ; Easterbrook, Philippa ; Feld, Jordan J. ; Ghany, Marc ; Janssen, Harry L.A. ; Korenjak, Marko ; Lampertico, Pietro ; Lee, Hannah ; Liang, Jake ; Lok, Anna S. ; Negro, Francesco ; Rehermann, Barbara ; Sheikh, Virginia ; Papatheodoridis, George ; Petersen, Jӧrg ; Terrault, Norah ; Younossi, Zobair M. ; Yuen, Man-Fung</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c3152-d118a5c33b4a1c00bf4b500bef30c5f4057a96e7c66d03b12add27aff248a553</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2023</creationdate><topic>Antiviral Agents - 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Conference participants reached agreement on some key points. The preferred primary endpoint for phase II/III trials evaluating finite treatments for chronic hepatitis B (CHB) is “functional” cure, defined as sustained HBsAg loss and HBV DNA less than lower limit of quantification (LLOQ) 24 weeks off-treatment. An alternate endpoint would be “partial cure” defined as sustained HBsAg level <100 IU/mL and HBV DNA <LLOQ 24 weeks off-treatment. Clinical trials should initially focus on patients with HBeAg-positive or negative chronic hepatitis B, who are treatment-naїve or virally suppressed on nucleos(t)ide analogues. Hepatitis flares may occur during curative therapy and should be promptly investigated and outcomes reported. HBsAg loss would be the preferred endpoint for chronic hepatitis D, but HDV RNA <LLOQ 24 weeks off-treatment is a suitable alternate primary endpoint of phase II/III trials assessing finite strategies. For trials assessing maintenance therapy, the primary endpoint should be HDV RNA <LLOQ assessed at on-treatment week 48. An alternate endpoint would be ≥2 log reduction in HDV RNA combined with normalization of alanine aminotransferase (ALT) level. Suitable candidates for phase II/III trials would be treatment-naїve or -experienced patients with quantifiable HDV RNA. Novel biomarkers (HBcrAg, HBV RNA) remain exploratory while nucleos(t)ide analogues and pegylated interferon still have a role in combination with novel agents. Importantly, patient input is encouraged early on in drug development under the FDA/EMA patient-focused drug development programs.</abstract><cop>Netherlands</cop><pub>Elsevier B.V</pub><pmid>37377088</pmid><doi>10.1016/j.jhep.2023.06.002</doi><tpages>16</tpages><oa>free_for_read</oa></addata></record> |
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| ispartof | Journal of hepatology, 2023-11, Vol.79 (5), p.1254-1269 |
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| source | MEDLINE; Elsevier ScienceDirect Journals |
| subjects | Antiviral Agents - therapeutic use Biomarkers Cirrhosis Clinical Outcomes Clinical Trials as Topic - methods Clinical Trials, Phase II as Topic - methods Cure DNA, Viral - analysis DNA, Viral - blood Endpoint Determination - methods Hepatitis B Surface Antigens - blood Hepatitis B virus - genetics Hepatitis B, Chronic - drug therapy Hepatitis B, Chronic - therapy Hepatitis B, Chronic - virology Hepatitis D, Chronic - drug therapy Hepatitis Delta Virus - genetics Humans Novel therapy Research Design Treatment Outcome |
| title | 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 |
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