Individualising endpoints in chronic HBV treatment: HBsAg loss and beyond

There are many new compounds in development for the treatment of chronic hepatitis B (CHB). Although major on-treatment declines in hepatitis B surface antigen (HBsAg) can be achieved with some of these drugs, achieving sustained post-treatment HBsAg loss with undetectable HBV DNA (functional cure) remains challenging, particularly in patients with high pretreatment HBsAg levels. Interestingly, a substantial proportion of patients in these trials who did not achieve HBsAg loss did maintain low HBsAg levels after withdrawal of study treatments. Based on data from natural history studies and studies on finite treatment with currently available agents, off-treatment sustained low HBsAg levels with low or undetectable HBV DNA levels (referred to as partial cure) is associated with excellent virological and clinical outcomes. In this expert opinion article, we argue that it is important to shift focus from HBsAg loss as the sole endpoint of HBV trials to a more individualised assessment of response that also considers partial cure (defined as off-treatment sustained low HBsAg with undetectable HBV DNA, potentially combined with other biomarkers) as a favourable treatment outcome. Such an approach could increase the number of patients considered responders and, in doing so, potentially extend eligibility for novel therapies to more patients with CHB who may derive significant clinical benefit.