Adefovir for chronic hepatitis B treatment: identification of virological markers linked to therapy response.

BACKGROUND: HBV variants rtA181V/T, rtN236T and rtl233V, which confer resistance to adefovir dipivoxil (ADV), are not detected in many non-responding patients. Virological characteristics useful for predicting response have not been clearly elucidated. We determined pretreatment virological markers to predict non-response and possible emergence of new variants during therapy.
METHODS: This longitudinal study included 41 patients with chronic hepatitis B virus (HBV) infection receiving ADV monotherapy or ADV plus lamivudine (3TC). A fragment of HBV polymerase including catalytic domains was analysed for ADV-resistant variants.
RESULTS: Complete virological response (CVR; HBV DNA < 2.5 log10 copies/ml) was observed in 15 (36.6%) patients and partial virological response (PVR; HBV DNA < 4 log, copies/ml) in 23 (56.1%) patients. On multivariate analyses, hepatitis B e antigen (HBeAg) status was independently associated with CVR (hazard ratio [HR] = 0.27, P = 0.002) and PVR (HR = 0.21, P < 0.001) and viral genotype with CVR (HR = 0.13, P = 0.01). Predictive values for HBeAg were 88% for PVR in HBeAg-negative and 79% for non-CVR in HBeAg-positive patients. Predictive values for viral genotype were 93% for non-CVR and 72% for non-PVR for genotype A. On sequencing, variant rt217R (associated with subgenotype A2) was predictive of non-CVR (100%) and non-PVR (72.7%); the rtS219A variant emerged during therapy in three non-PVR patients. Both positions are located in a region likely to be related to the substrate union site, as predicted by our structural model of the HBV polymerase.
CONCLUSIONS: Virological pretreatment characteristics (HBeAg, viral genotype and rtL217R polymorphism) are potentially associated with ADV response. HBV polymerase structural modelling has provided a hypothesis to explain the molecular mechanism for ADV resistance associated with rtR217.