This is a phase IV, single-arm, open-label, multi-centre study to assess the efficacy of TDF in Chronic hepatitis B (CHB) subjects following failure of multiple Nucleos(t)ide analogues (NAs). The study will enrol 200 CHB subjects following failure of multiple NAs. Subjects will be assessed for eligibility at a screening visit, with eligible subjects returning for a baseline assessment after approximately 4 weeks (Screening phase). In the treatment phase all enrolled subjects will receive open label TDF at a dose of 300 milligrams (mg) orally once daily. All the eligible study subjects will undergo safety and efficacy assessments every 12 weeks for a total of 14 visits. Tenofovir disoproxil fumarate, the oral pro-drug of tenofovir (TFV), is a nucleotide analogue that inhibits viral polymerases by direct binding and after incorporation into deoxyribonucleic acid (DNA), by termination of the DNA) chain. TDF is a highly potent treatment in treatment-naïve and lamivudine (LAM) resistant CHB patients. The purpose of our study is to evaluate the efficacy of TDF treatment in Chinese CHB patients following failure of multiple NAs. In addition, the study will also explore the relationship of baseline factors and early HBV DNA suppression to long-term virological response. The efficacy of TDF in multi-drug resistant patients will be analysed separately. The data generated by this study could then be used to optimize the clinical application of TDF and provide new evidence for management of the HBV infections following failure of multiple NAs. The result of this study will help Chinese physicians better manage the CHB patients following failure of multiple NAs.