IN A NEW expert analysis, hepatology researchers are calling for a strategic shift in how clinical trials and clinicians define successful treatment for chronic hepatitis B (CHB). While complete loss of hepatitis B surface antigen (HBsAg), often termed “functional cure”, has long been considered the gold-standard endpoint, the authors argue that this narrow focus is no longer aligned with therapeutic realities or emerging evidence.
Functional Cure Remains Ideal, but Rare
HBsAg clearance with undetectable HBV DNA is durable, reduces hepatocellular carcinoma (HCC) risk, and eliminates the need for lifelong antiviral therapy. However, despite newer RNA interference agents, antisense oligonucleotides, nucleic acid polymers, and immunomodulatory combinations, sustained HBsAg loss is achieved in only a minority of treated patients. Rates remain particularly low in patients entering therapy with high HBsAg levels, prompting trial designs skewed toward highly selected populations.
Value of “Partial Cure” Emerging
A key insight highlighted by the authors is that many patients who do not clear HBsAg still maintain very low HBsAg levels after stopping therapy, an outcome linked to excellent clinical trajectories.
Natural history studies and data from finite-treatment trials show that individuals with HBsAg <100 IU/mL and undetectable HBV DNA have: negligible risk of developing active hepatitis, extremely low annual HCC incidence, and a high likelihood of eventual spontaneous HBsAg clearance. These patients appear clinically indistinguishable from those who achieve full HBsAg loss.
Reframing Trial Endpoints
The authors propose formally recognizing this state, termed partial cure, as an acceptable and clinically meaningful endpoint. Doing so would expand the proportion of patients considered responders, reduce attrition of promising therapies, and align outcomes with real-world disease biology.
A More Individualized Future
The authors urge HBV clinical trials to include partial cure in all future outcome reporting, enabling more nuanced therapeutic assessments and more patient-centered treatment decision-making.
Reference
Sonneveld MJ, Janssen HLA. Individualizing Endpoints in Chronic HBV Treatment: HBsAg Loss and Beyond. J Hepatol. 2025;DOI:10.1016/j.jhep.2025.12.006.
