title: 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 Conventional interferon alpha (IFN-α), the only agent licensed in 1991, has been superseded by pegylated IFN-α.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.
authors.affiliation: Department of Medicine, the University of Hong Kong, Queen Mary Hospital, China. mfyuen@hkucc.hku.hk
authors.forename: Man-Fung
authors.initials: MF
authors.lastname: Yuen
authors.forename: Ching-Lung
authors.initials: CL
authors.lastname: Lai
mesh_terms: D000998:Antiviral Agents / Q000627:therapeutic use*; D015415:Biomarkers / Q000097:blood; D006528:Carcinoma, Hepatocellular / Q000517:prevention & control / Q000821:virology; D004279:DNA, Viral / Q000097:blood; D024882:Drug Resistance, Viral; D004359:Drug Therapy, Combination; D006513:Hepatitis B e Antigens / Q000097:blood; D006515:Hepatitis B virus / Q000235:genetics / Q000276:immunology / Q000472:pathogenicity*; D019694:Hepatitis B, Chronic / Q000150:complications / Q000175:diagnosis / Q000188:drug therapy*; D006801:Humans; D008113:Liver Neoplasms / Q000517:prevention & control / Q000821:virology; D013997:Time Factors; D016896:Treatment Outcome; D019562:Viral Load
chemical_list: D000998:Antiviral Agents; D015415:Biomarkers; D004279:DNA, Viral; D006513:Hepatitis B e Antigens