Adefovir Dipivoxil for the Treatment of Hepatitis B e Antigen–Negative Chronic Hepatitis B
Stephanos J. Hadziyannis, M.D., Nicolaos C. Tassopoulos, M.D., E. Jenny Heathcote, M.D., Ting-Tsung Chang, M.D., George Kitis, M.D., Mario Rizzetto, M.D., Patrick Marcellin, M.D., Seng Gee Lim, M.D., Zachary Goodman, M.D., Michael S. Wulfsohn, M.D., Ph.D., Shelly Xiong, Ph.D., John Fry, B.Sc., Carol L. Brosgart, M.D., for the Adefovir Dipivoxil 438 Study Group
Background Adefovir dipivoxil, a nucleotide analogue, demonstratedclinically significant antiviral activity in patients with chronichepatitis B in phase 1 and 2 clinical trials.
Methods We randomly assigned 185 patients with chronic hepatitisB who were negative for hepatitis B e antigen (HBeAg) to receiveeither 10 mg of adefovir dipivoxil or placebo once daily for48 weeks in a 2:1 ratio and a double-blind manner. The primaryend point was histologic improvement.
Results At week 48, 64 percent of patients who had base-lineliver-biopsy specimens available in the adefovir dipivoxil grouphad improvement in histologic liver abnormalities (77 of 121),as compared with 33 percent of patients in the placebo group(19 of 57, P<0.001). Serum hepatitis B virus (HBV) DNA levelswere reduced to fewer than 400 copies per milliliter in 51 percentof patients in the adefovir dipivoxil group (63 of 123) andin 0 percent of those in the placebo group (0 of 61, P<0.001).The median decrease in log-transformed HBV DNA levels was greaterwith adefovir dipivoxil treatment than with placebo (3.91 vs.1.35 log copies per milliliter, P<0.001). Alanine aminotransferaselevels had normalized at week 48 in 72 percent of patients receivingadefovir dipivoxil (84 of 116), as compared with 29 percentof those receiving placebo (17 of 59, P<0.001). No HBV polymerasemutations associated with resistance to adefovir were identified.The safety profile of adefovir dipivoxil was similar to that of placebo.
Conclusions In patients with HBeAg-negative chronic hepatitisB, 48 weeks of adefovir dipivoxil treatment resulted in significanthistologic, virologic, and biochemical improvement, with anadverse-event profile similar to that of placebo. There wasno evidence of the emergence of adefovir-resistant HBV polymerasemutations.
Source Information
From the Department of Medicine and Hepatology, Henry Dunant Hospital, Athens, Greece (S.J.H.); Western Attica General Hospital, Athens, Greece (N.C.T.); Toronto Western Hospital, University of Toronto, Toronto (E.J.H.); the Department of Internal Medicine, National Cheng Kung University Hospital, Tainan, Taiwan (T.-T.C.); Georgios Papanikolaou Hospital, Thessaloniki, Greece (G.K.); Azienda Ospedaliera San Giovanni Battista, Turin, Italy (M.R.); Service d'Hépatologie, INSERM Unité 481, and Centre de Recherche Claude Bernard sur les Hépatites Virales, Hôpital Beaujon, Clichy, France (P.M.); the Division of Gastroenterology, National University Hospital, Singapore (S.G.L.); the Armed Forces Institute of Pathology, Washington, D.C. (Z.G.); and Gilead Sciences, Foster City, Calif. (M.S.W., S.X., J.F., C.L.B.).
Address reprint requests to Dr. Hadziyannis at the Department of Medicine, Henry Dunant Hospital, 107 Mesogion Ave., Athens 11526, Greece, or at hadziyannis{at}ath.forthnet.gr.
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