What is the optimum dose of adefovir in the treatment of chronic hepatitis B infection?
Authors: Halis Simsek, Ali Shorbagi, Yasemin Balaban, Gonca Tatar
Journal: Journal of Hepatology (2008)

The phosphonate nucleotide analogue adefovir (ADV), available as its prodrug adefovir dipivoxil, was initially introduced for the treatment of human immunodeficiency virus infection (dose 60–120 mg), but later gained the attention of the hepatology community for its role in the treatment of naïve chronic hepatitis B patients, and later on lamivudine (LVD) resistant chronic hepatitis B, albeit at a much lower dose. Till today, a shadow of doubt remains on the truly optimum dose of adefovir in the treatment of chronic hepatitis B infection. An early phase I/II study [[1]Gilson R.J. Chopra K.B. Newell A.M. Murray-Lyon I.M. Nelson M.R. Rice S.J. et al.A placebo-controlled phase I/II study of adefovir dipivoxil in patients with chronic hepatitis B virus infection.J Viral Hepat. 1999; 6: 387-395Crossref PubMed Scopus (111) Google Scholar] had established the rapid efficacy of ADV (dose 125 mg) in inhibiting viral activity as well as decreasing liver transaminases. However, the short duration of treatment (4 weeks) adopted in this study failed to ascertain the renal toxicity that the drug has notoriously become famous for, which has been shown to come into effect after 20 weeks of use. Following the open-label pilot study by Benhamou et al. [[2]Benhamou Y. Bochet M. Thibault V. Calvez V. Fievet M.H. Vig P. et al.Safety and efficacy of adefovir dipivoxil in patients co-infected with HIV-1 and lamivudine-resistant hepatitis B virus: an open-label pilot study.Lancet. 2001; 358: 718-723Abstract Full Text Full Text PDF PubMed Scopus (303) Google Scholar], 10 mg became the universally accepted treatment dose for chronic hepatitis B infection. This was later consolidated after the results of analysis on the renal safety of ADV 10 mg and 30 mg daily for the treatment of patients with chronic hepatitis B from two major studies were published [[3]Izzedine H. Hulot J.S. Launay-Vacher V. Marcellini P. Hadziyannis S.J. Currie G. et al.Renal safety of adefovir dipivoxil in patients with chronic hepatitis B: two double-blind, randomized, placebo-controlled studies.Kidney Int. 2004; 66: 1153-1158Crossref PubMed Scopus (152) Google Scholar], where it was established that the incidence of ADV nephrotoxicity was indeed dose-related particularly for all doses ⩾30 mg daily, while there was no evidence of this toxicity at the currently approved dose. However, a more recent publication [[4]Hezode C. Chevaliez S. Bouvier-Alias M. Roudot-Thoraval F. Brillet R. Zafrani E.S. et al.Efficacy and safety of adefovir dipivoxil 20 mg daily in HBeAg-positive patients with lamivudine-resistant hepatitis B virus and a suboptimal virological response to adefovir dipivoxil 10 mg daily.J Hepatol. 2007; 46: 791-796Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar] echoed the ever resonant voices of many authors who feel that this dose led to a “suboptimal” and sometimes even disappointing viral response. In this report, Hezode et al. concluded that suboptimal responses to 10 mg daily were due to “underdosing”, and that increasing the dose to 20 mg daily was “beneficial and safe in patients with LVD-resistant hepatitis B”, especially when alanine aminotransferase levels are elevated and/or liver disease is severe or rapidly progressive while on 10 mg daily. Our experience with ADV as a monotherapy for chronic hepatitis B, at a standard dose of 10 mg, has been short of disappointing. In a particular case of a 39-year-old male patient with persistent HbeAg positivity, no sustainable biochemical or viral response was achieved despite treatment with several agents over a 10 year follow-up period in our clinic (Fig. 1). After an initial ADV dose of 10 mg daily failed to impress, the dose was increased to 20 mg daily in June 2007, resulting in a logarithmic decrease in viral count as well as a biochemical response, with no detrimental effects on renal function. An excellent review by Sheperd et al. [[5]Shepherd J. Jones J. Takeda A. Davidson P. Price A. Adefovir dipivoxil and pegylated interferon alfa-2a for the treatment of chronic hepatitis B: a systematic review and economic evaluation.Health Technol Assess. 2006; 10: 1-183Crossref Scopus (67) Google Scholar] evaluated the clinical efficacy and cost-effectiveness of ADV treatment for chronic hepatitis B, with monotherapy response rates reported at between 21 and 51%. Response rates are even lower in LVD resistant cases, with a reported ADV resistance of 25% after 24 months of treatment [[6]Yeon J.E. Yoo W. Hong S.P. Chang Y.J. Yu S.K. Kim J.H. et al.Resistance to adefovir dipivoxil in lamivudine resistant chronic hepatitis B patients treated with adefovir dipivoxil.Gut. 2006; 55: 1488-1495Crossref PubMed Scopus (163) Google Scholar]. In light of these findings, we believe that a 10 mg daily dose of ADV is indeed insufficient in satisfactorily controlling chronic hepatitis B infection, especially in the setting of LVD resistance. If it is to be recommended at all, we advocate that it should be used at an initial dose of 20 mg, albeit with careful and close monitoring of renal functions.