The scientific basis of combination therapy for chronic hepatitis B functional cure

• Published in: Nature reviews. Gastroenterology & hepatology 2023-04, Vol.20 (4), p.238-253
• Main Authors: Lim, Seng Gee, Baumert, Thomas F., Boni, Carolina, Gane, Ed, Levrero, Massimo, Lok, Anna S., Maini, Mala K., Terrault, Norah A., Zoulim, Fabien
• Format: Article
• Language: English
• Subjects: 631/250/255/234/2513/1549; 692/4020/4021/234/2513/1549; Antigens; Antiviral Agents - therapeutic use; Biomedicine; Combination therapy; Combined Modality Therapy; DNA, Viral - therapeutic use; Gastroenterology; Hepatitis B; Hepatitis B e Antigens; Hepatitis B surface antigen; Hepatitis B Surface Antigens; Hepatitis B virus - genetics; Hepatitis B, Chronic - drug therapy; Hepatology; Human health and pathology; Humans; Immunology; Immunotherapy; Interferon; Life cycles; Life Sciences; Medicine; Medicine & Public Health; Review Article; Treatment Outcome
• ISSN: 1759-5045; 1759-5053; 1759-5053
• DOI: 10.1038/s41575-022-00724-5

Functional cure of chronic hepatitis B (CHB) — or hepatitis B surface antigen (HBsAg) loss after 24 weeks off therapy — is now the goal of treatment, but is rarely achieved with current therapy. Understanding the hepatitis B virus (HBV) life cycle and immunological defects that lead to persistence can identify targets for novel therapy. Broadly, treatments fall into three categories: those that reduce viral replication, those that reduce antigen load and immunotherapies. Profound viral suppression alone does not achieve quantitative (q)HBsAg reduction or HBsAg loss. Combining nucleos(t)ide analogues and immunotherapy reduces qHBsAg levels and induces HBsAg loss in some patients, particularly those with low baseline qHBsAg levels. Even agents that are specifically designed to reduce viral antigen load might not be able to achieve sustained HBsAg loss when used alone. Thus, rationale exists for the use of combinations of all three therapy types. Monitoring during therapy is important not just to predict HBsAg loss but also to understand mechanisms of HBsAg loss using viral and immunological biomarkers, and in selected cases intrahepatic sampling. We consider various paths to functional cure of CHB and the need to individualize treatment of this heterogeneous infection until a therapeutic avenue for all patients with CHB is available. In this Review, the authors consider various paths to functional cure of chronic hepatitis B (CHB) and the need to individualize therapy of this heterogeneous infection until a therapeutic avenue for all patients with CHB is available. Key points Functional cure is defined as loss of hepatitis B surface antigen (HBsAg) and undetectable hepatitis B virus (HBV) DNA after 6 months off therapy; it is associated with improved clinical outcomes and is the optimal goal of therapy for chronic hepatitis B. Novel agents fall into three categories: those that reduce viral replication, those that reduce viral antigen load and immunotherapies; combinations that lead to functional cure are being explored. Profound viral suppression alone is unlikely to lead to functional cure or reduction in quantitative (q)HBsAg levels. Combining replication inhibition with immunotherapy leads to some reduction in qHBsAg levels (