Combination Therapy for Chronic Hepatitis B: Current Updates and Perspectives

Abstract

Nucleos(t)ide analogues (NUCs) and interferon have been used for several decades to treat chronic hepatitis B; however, the therapeutic response remains unsatisfactory. Although NUC therapy exhibits potent on-treatment viral suppression, frequent off-therapy virological relapses suggest an indefinite treatment course. Interferon modulates the innate and adaptive antiviral immune responses and thus increases the chance of viral eradication. Interferon therapy has the advantage of a finite duration, absence of drug resistance, and durable posttreatment responses. Therefore, the combination of NUCs and interferon can theoretically facilitate a synergistic therapeutic effect. This paper summarizes the current strategies of various combination therapies into three categories: the simultaneous "dual" strategy, sequential combination "add-on" strategy, and "switch" strategy. Generally, dual therapy exhibits greater on-treatment and off-therapy viral suppression and lower drug resistance compared with NUC monotherapy. Compared with interferon monotherapy, dual therapy has greater on-treatment viral suppression but shows no difference in off-therapy sustained virological responses. Specific add-on or switch strategies provide promising on-treatment efficacy in select patients. Pretreatment or on-treatment quantitative hepatitis B surface antigen and e antigen are predictive for the treatment efficacy of combination therapy. The optimal schedule of combination regimens and individualized therapy remain to be comprehensively evaluated.

Keywords: Add-on; Dual; Interferons; Nucleos(t)ide analogue; Switch.

Fig. 1

Diagram of combination therapy. Dual therapy is defined as the concurrent use of nucleos(t)ide analogues (NUCs) and interferon (IFN) during the entire treatment course. Add-on therapy is defined as a sequential combination of NUCs and pegylated IFN (PegIFN), whereby the combination is employed for more than 12 weeks, with two types of combinations: NUC-based therapy with add-on PegIFN and PegIFN-based therapy with add-on NUCs. Switch therapy is defined as a long-term NUC or PegIFN therapy with a subsequent switch to PegIFN or NUCs, with or without a short period (≤12 weeks) of overlap of both agents.