• INCLUSION CRITERIA (nucleoside analogue-naive subjects):
• Age greater than 18 years and older, male or female.
• Known serum HBsAg positivity for 24 weeks.
• Detectable HBV DNA greater than 10(5) copies per ml.
• Serum ALT or AST levels 1.5 times the upper limit of normal (for ALT: greater than or equal to 62 U/L and for AST greater than or equal to 46 U/L) based on at least two determinations taken at least one month apart during the 24 weeks before study entry.
• Liver biopsy within 2 years of entry that is consistent with chronic hepatitis and with a histology activity index (HAI) score of 4 or more (scores range from 0-18) and an Ishak fibrosis score of at least 1 (scores range from 0-6). For patients who have had a liver biopsy at another institution, slides must be obtained for reading and scoring at the NIH.
• Written informed consent.

INCLUSION CRITERIA: SALVAGE STUDY (nucleoside analogue experienced subjects)

• Age greater than 18 years and older, male or female.
• Known serum HBsAg positivity for 6 months.
• Detectable HBV DNA greater than 10(2) copies per milliliter.
• Liver biopsy within 2 years of entry that is consistent with chronic hepatitis and with a histology activity index (HAI) score of 4 or more (scores range from 0-18) and an Ishak fibrosis score of at least 1 (scores range from 0-6).
• Written informed consent.

EXCLUSION CRITERIA:

• Previous or current treatment with tenofovir or emtricitabine.
• Co-infection with HDV as defined by the presence of anti-HDV in serum and/or HDV antigen in the liver.
• Co-infection with HCV as defined by the presence of HCV RNA in serum.
• Co-infection with HIV as defined by the presence of anti-HIV in serum.
• Decompensated liver disease as defined by serum bilirubin greater than 2.5 milligram per deciliter (with direct bilirubin greater than 0.5 milligram per deciliter), prothrombin time of greater than 2 seconds prolonged, a serum albumin of less than 3 grams per deciliter, or a history of ascites, variceal bleeding or hepatic encephalopathy.
• Presence of other causes of liver disease (i.e. hemochromatosis, Wilson disease, alcoholic liver disease, nonalcoholic steatohepatitis, alpha-1anti-trypsin deficiency).
• A history of organ transplantation or in the absence of organ transplantation, any immunosuppressive therapy requiring the use of more than 5 milligrams of prednisone (or its equivalent) daily.
• Significant systemic illness other than liver diseases including congestive heart failure, renal failure, chronic pancreatitis, diabetes mellitus with poor control that in the opinion of the investigator may interfere with therapy.
• Pregnancy or inability to practice contraception in patients capable of bearing or fathering children and lactating women.
• Hepatocellular carcinoma (HCC), or the presence of a mass on imaging studies of the liver that is suggest of HCc, or an alpha-fetoprotein level of greater than 500ng/mL.
• History of clinically apparent pancreatitis or evidence of subclinical pancreatitis as shown by serum amylase values twice the upper limits of the normal range and abnormalities of the pancreas on CT or other imaging studies of the abdomen.
• Sensory or motor neuropathy apparent from medical history and physical examination.
• Creatinine clearance less than 50 ml/min, serum creatinine greater than 1.3 mg/dl or urine protein greater than 1 gram/24 hours; creatinine clearance will be determined on the average of two 24 hour urine specimens. Accuracy of collection will be ensured by documenting appropriate total creatinine excretion in the 24 hour urine specimen (15mg/kg) and correcting for the patient's age, gender and body surface area.
• Concurrent use of nephrotoxic agents (e.g. aminoglycosides, amphotericin B, vancomycin, foscarnet, cis-platinum, pentamidine, nonsteroidal anti-inflammatory agents) or competitors of renal tubular excretion (e.g. probenecid) within 2 months prior to study screening or the expectation that the subject will receive these during the course of the study.
• History of hypersensitivity to nucleoside analogues.
• Active ethanol/drug abuse/psychiatric problems such as major depression, schizophrenia, bipolar illness, obsessive-compulsive disorder, severe anxiety, personality disorder that, in the investigator's opinion, might interfere with participation in the study.
• History of renal tubular acidosis.
• History of malignancy or treatment for a malignancy within the past 5 years.
• Presence of conditions that, in the opinion of the investigators, would not allow the patient to be followed in the current study for at least 5 years.