Evolution of Therapy for Chronic Hepatitis B: Progressing from the Simple to the Complex

In the past decade, physicians treating chronic hepatitis B have gained the luxury of choice. The U.S. Food and Drug Administration has approved 6 drugs for treating chronic hepatitis B (listed in order of approval date): interferon-α2b, lamivudine, adefovir, entecavir, pegylated interferon-α2a, and telbivudine (1). The introduction of nucleoside and nucleotide analogues has revolutionized therapy for chronic hepatitis B. Unlike interferon, these agents are orally administered, well tolerated, safe, and very effective at suppressing hepatitis B virus (HBV) replication. They improve liver disease and reduce rates of liver transplantation and hepatocellular carcinoma (2, 3). However, because viral replication usually resumes after treatment with nucleoside and nucleotide analogues is stopped, long-term, perhaps indefinite, administration is essential (4, 5). Unfortunately, long-term treatment usually brings viral resistance to drugs and, consequently, loss of clinical response, occasional flares of hepatitis, and sometimes death (6, 7).

The wider choice of antiviral agents has raised new questions: which ones to use, how long to use them, what constitute suitable end points, and when to change therapy. The ultimate goal of therapy is to prevent the long-term complications of chronic hepatitis B: cirrhosis, decompensated liver disease, and hepatocellular carcinoma. Unfortunately, these end points are impractical for clinical trials and for measuring success in individual patients. Instead, investigators use surrogate end points. They define response by several variables: virologic (undetectable HBV DNA by a sensitive polymerase chain reaction–based assay or loss of hepatitis B e antigen [HBeAg] or hepatitis B surface antigen [HBsAg]), biochemical (normalization of serum alanine aminotransferase [ALT] levels), and histologic (2-point decrease in the histologic activity index score with no worsening of fibrosis) (8). The timing of response is also important and is described as initial, maintained (on therapy), or sustained (off therapy) (8). By using these definitions, we …