R E V I E W A RTICLE Hepatitis Monthly 2010; 10(1): 42-47 Molecular Diagnosis of Entecavir Resistance Murat Sayan* Faculty of Medicine, University of Kocaeli, Kocaeli, Turkey Entecavir (ETV) is a potent nucleoside analogue against hepatitis B virus (HBV). Because of development of ETV resis- tance requires at least three amino acid substitutions in HBV polymerase (pol) gene, emergence of ETV resistance is rare (~1%) in nucleoside-naive patients after up to 5 years of treatment. However, it has been suggested that lamivudine (LAM) therapy can preselect for HBV variants associated with resistance to ETV treatment. ETV resistance increased to 51% of patients after 5 years of ETV treatment in LAM refractory patients. The diagnosis of ETV resistance in chronic hepatitis B patients, mainly based on four types of molecular assays: direct sequencing, line probe assay, clonal analysis, and restriction fragment length polymorphism (RFLP) analysis. The applications of other assays are currently more spe- cialized, and their use is more limited. The utility of these assays and their performance characteristics are reviewed be- low. Briefly, the monitoring of drug-resistant variants is important in the elucidation of the prevalence and mechanisms of resistance development and for the more effective management of treatment options. Keywords: Entecavir, Chronic Hepatitis B, Nucleoside Analogue, Entecavir Resistance, Molecular Diagnosis Introduction Ivaccine, approximately one third of the n spite of the availability of a highly effective world’s population has serological findings of past or present infection with hepatitis B virus (HBV); and globally, over 350 million people are currently chronically infected. The spectrum of disease and the natural history of chronic HBV infection is diverse and variable, ranging from inactive-carrier state to progressive chronic hepatitis, which may evolve to cirrhosis and hepatocellular carcinoma (HCC) (1). Two different types of drugs can be used in the treatment of chronic hepatitis B (CHB): interferon alpha and nucleoside/nucleotide analogues (NUCs). NUCs for HBV therapy belong to three subclasses: L-nucleosides, i.e. lamivudine (LAM), telbivudine (LdT), and emtricitabine (FTC), deoxyguanosine analogues, i.e. entecavir (ETV) and acyclic nucleoside phosphonates, i.e. adefovir (ADV) and tenofovir (TDF). LAM, LdT, ETV, ADV, TDF and FTC have been approved in Europe, the United States, and most Asian and Latin American countries for HBV treatment (1, 2). The emergence of mutations should be expect ed from HBV genome characteristics. The major causes of drug resistance include viral factors such as the kinetics of viral production and clearance; lack of a proofreading mechanism during reverse transcription, which creates a large HBV quasispecies pool, and the replication fitness of the viral quasispecies (3, 4). However, a major concern with NUC treatment is the selection of antiviral – resistant mutations. Long- term therapy with NUCs, especially, is associated with an increased risk of the development of drug resistance (5, 6). Mutations selected under NUCs can be split into two groups : those that cause resistance that sometimes leads to a decreased viral fitness, and compensatory mutations, which partially or fully restore the level of viral fitness (7, 8). * Correspondence: Murat Sayan, Ph.D. Clinical Laboratory, Faculty of Medicine, Umuttepe Kampus, University of Kocaeli, 41340, İzmit – Kocaeli, Turkey. Tel: +90 262 303 8571 Fax: +90 262 303 8085 E-mail: sayanmurat@hotmail.com Received: 21 Nov 2009 Accepted: 14 Jan 2010 Hepat Mon 2010; 10 (1): 42-47 Revised: 11 Jan 2010