1Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA.
2Liver Unit, Hospital Universitario Valle Hebron, Barcelona.
3Division of Gastroenterology and Hepatology, Milan, Italy; CRC "A. M. and A. Migliavacca" Center for Liver Disease, Milan, Italy.
4Stravitz- Sanyal Institute for Liver Disease and Metabolic Health; Department of Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University, Richmond, VA, USA.
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-naïve 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-naïve 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.