[Analogs combination therapy in chronic hepatitis B: when and how?]

Hepatitis B virus (HBV) genomic variability is responsible for the complexity of the viral quasi-species and its evolution during the course of infection. The persistence of infected cells promotes the selection of drug-resistant strains. The development of nucleoside analogs without cross-resistance has provided a rationale for combination therapy. De novo combination, with low genetic barrier drugs, prevents the emergence of resistance in the short-term for drugs with a low genetic barrier and improves the control of infection. Long-term studies are needed to determine whether de novo combination is beneficial for analogs with a high genetic barrier as well. The add-on strategy is a standard in case of emergence of resistant mutants. This strategy needs to be implemented as early as possible before the virological breakthrough, especially if the viral suppression is sub-optimal. Clinical trials are mandatory in order to assess whether a) de novo combination is better than an early add-on strategy; and b) whether in case of sub-optimal viral suppression, an early add-on strategy is better in the long-term than a switch to a more potent drug with a high genetic barrier.