Treatment of chronic hepatitis B: Evolution over two decades

Abstract There has been a recent paradigm shift in the indications and endpoints of treatment for chronic hepatitis B (CHB). Hepatitis B e antigen (HBeAg)‐negative disease is being increasingly recognized. Antiviral treatment for both HBeAg‐positive and HBeAg‐negative patients should aim at long‐term suppression of HBV DNA, with the ultimate ideal endpoint of hepatitis B surface antigen (HBsAg) seroconversion. Conventional interferon alpha (IFN‐α), the only agent licensed in 1991, has been superseded by pegylated IFN‐α. HBeAg seroconversion using pegylated IFN‐α is 33%, with only 25% of HBeAg‐positive patients achieving undetectable HBV DNA by polymerase chain reaction (PCR) assay. Five nucleoside/nucleotide analogues have been licensed since 1998. Lamivudine, an L‐nucleoside, is limited by the development of resistance in 76% of patients after 5 years of therapy. Telbivudine, another L‐nucleoside, is more potent than lamivudine but resistance still develops in 25% of HBeAg‐positive and 11% HBeAg‐negative patients after 2 years. Adefovir, an acyclic phosphonate, is relatively weak, but is effective against lamivudine‐ and telbivudine‐ resistant mutations, for which it should be used in combination (add‐on therapy) rather than substituted. Resistance to adefovir develops slowly, rising to 29% for HBeAg‐negative patients by year 5, but more rapidly when used alone for lamivudine‐resistant HBV. Currently the two first line nucleoside/nucleotides are entecavir and tenofovir. Entecavir, a cyclopentane (D‐nucleoside), is very potent, with 94% of patients having undetectable HBV DNA after 5 years. Resistance develops in only 1.2% of treatment‐naïve patients. Tenofovir, another acyclic nucleotide, is more potent with less renal toxicity compared to adefovir. It is effective against lamivudine‐resistant mutations when used alone. No resistance to tenofovir has been described after its use for 3 years or longer, often for patients with human immunodeficiency virus/HBV co‐infection. With these current, potent antiviral agents associated with very low rates of resistance, long‐term HBV DNA suppression and possibly even reversal of cirrhosis can now be achieved in a proportion of patients. In addition, long‐term treatment with these antiviral agents is associated with a reduced risk of development of hepatocellular carcinoma.