Groupe hospitalier Pitié-Salpêtrière-CERVI, Laboratoire de virologie, 83, boulevard de l'hôpital, 75651 Paris cedex 13, France
Prolonged treatment with orally available antiviral treatments for chronic hepatitis B lead very often to selection of diminished sensitivity strains to these molecules. Clinical consequences of treatment breakthrough can bevery severe. Parameters linked to the host, such as the immune response, to treatments, such as their efficacy to control viral replication or to the virus itself, such as its mode of replication and its genetic arrangement explain the kinetic of resistance emergence and the very nature of the variant strains. For all molecules but tenofovir, different genetic mutation patterns on viral strains have been characterized that modify their intrinsic sensitivity to antivirals. A thorough definition of resistance should be followed in order to draw a link between a clinical situation, a specific mutational pattern and an in vitro phenotypic susceptibility. Several laboratory tools with unequal and specific performance are available; their proper use should prevent the abusive description of irrelevant resistant variants with no clinical implication. Once a strong link between phenotypic and genotypic resistance is established, virology laboratories can determine the genetic sequence of an emerging strain in order to help the clinician for the next best therapeutic choice. Empirical and in vitro oriented experiences have demonstrated cross resistance between several antivirals and have led to the actual recommendations to associate molecules from different chemical classes in order to prevent resistance. Due to overlapping reading frames in the HBV genome, mutations known to confer resistance by modifying polymerase amino-acids may also affect the surface protein HBs. These latter modifications may alter HBsAg antigenicity or conformation with potential clinical consequences, such as lack of vaccine induced antibody recognition of this newly generated variant. Surveillance is needed to assess if this problem may pose some threat in the future. Low resistance rate observed with the newest molecules is rather good news. However, requirement of long term treatment to treat chronic hepatitis B should rely on an adequate manipulation of the few available molecules. Improper use of antivirals will inexorably lead to the emergence of potentially deleterious variants.