Correspondence

Adefovir Dipivoxil for Hepatitis B e Antigen–Positive Chronic Hepatitis B

N Engl J Med 2003; 348:2468June 12, 2003

Article

To the Editor:

I am concerned about the justification for the inclusion of a placebo group in the study by Marcellin et al. (Feb. 27 issue).1 No statement regarding the efficacy of interferon alfa was provided, although its side effects were highlighted. Surprisingly, a study that is often cited on this topic was not referenced.2 This study showed that eradication of hepatitis B e antigen (HBeAg) occurred in 33 percent of interferon-treated patients and the loss of hepatitis B virus (HBV) DNA occurred in 37 percent of interferon-treated patients, as compared with 12 percent and 17 percent of controls, respectively. In the study by Marcellin et al., the loss of HBeAg occurred in 11 percent of patients in the placebo group, and the eradication of HBV DNA occurred in none of the patients in that group.

A similar concern is related to the omission of lamivudine, which was approved by the Food and Drug Administration for HBeAg-positive patients in 1998. Resistance to lamivudine is rarely of clinical significance, and treatment with the drug can still result in improved results of liver tests and HBeAg seroconversion.3 Furthermore, a durable response has been reported in at least 73 percent of patients who become HBeAg-negative three months after discontinuing lamivudine therapy.4

The therapeutic armamentarium for chronic hepatitis B continues to expand. Before the conclusion of this study, patients in the placebo group should be offered treatment.

Sandeep Mukherjee, M.D.
University of Nebraska Medical Center, Omaha, NE 68198-3285
smukherjee@surgery.unmc.edu

4 References

1. 1

   Marcellin P, Chang T-T, Lim SG, et al. Adefovir dipivoxil for the treatment of hepatitis B e antigen-positive chronic hepatitis B. N Engl J Med 2003;348:808-816
   Full Text | Web of Science | Medline

2. 2

   Wong DKH, Cheung AM, O'Rourke K, Naylor CD, Detsky AS, Heathcote J. Effect of interferon treatment in patients with hepatitis B e antigen positive chronic hepatitis B: a meta-analysis. Ann Intern Med 1993;119:312-323
   Web of Science | Medline

3. 3

   Chang TT, Lai CL, Liaw YF, et al. Incremental increases in HBeAg seroconversion and continued ALT normalization in Asian chronic patients treated with lamivudine for four years. Antiviral Ther 2000;5:Suppl 1:44-44 abstract.
   

4. 4

   Liaw Y-F, Leung NWY, Chang TT, et al. Effects of extended lamivudine therapy in Asian patients with chronic hepatitis B. Gastroenterology 2000;119:172-180
   CrossRef | Web of Science | Medline

Author/Editor Response

The use of a placebo control in this study was necessary to distinguish the effects of adefovir dipivoxil therapy from the spontaneous progression of chronic hepatitis B. The study was designed and initiated before lamivudine was licensed. In this population, it was reasonable to delay the initiation of therapy for 48 weeks, since the risk of hepatic decompensation was low. Patients in the placebo group received adefovir dipivoxil during the second 48 weeks of the study, and all patients were offered adefovir dipivoxil after the study.

Interferon alfa has limited efficacy in various populations of patients with chronic hepatitis B.1 It is not possible to make comparisons with data from studies of interferon alfa therapy, because such studies used older, less sensitive assays that overestimate efficacy. Furthermore, a blinded comparison with interferon alfa therapy would not have been possible.

Long-term treatment with lamivudine is associated with a high incidence of resistance (16 to 32 percent after one year and 67 percent by four years), resulting in the loss of virologic, biochemical, serologic, and histologic responses in many patients and, in some cases, hepatic decompensation and death.2-4 Indeed, current treatment options are limited; new therapies such as adefovir dipivoxil are necessary.

Patrick Marcellin, M.D.
Hôpital Beaujon, 92110 Clichy, France
marcellin@bichat.inserm.fr

for the Adefovir Dipivoxil 437 Study Group

4 References

1. 1

   Wong DKH, Cheung AM, O'Rourke K, Naylor CD, Detsky AS, Heathcote J. Effect of alpha-interferon treatment in patients with hepatitis B e antigen positive chronic hepatitis B: a meta-analysis. Ann Intern Med 1993;119:312-323
   Web of Science | Medline

2. 2

   Liaw Y-F. Management of YMDD mutations during lamivudine therapy in patients with chronic hepatitis B. Gastroenterol Hepatol 2002;17:Suppl 3:S333-S337
   CrossRef

3. 3

   Dienstag JL, Goldin RD, Heathcote EJ, et al. Histologic outcome during long-term lamivudine therapy. Gastroenterology 2003;124:105-117
   CrossRef | Web of Science | Medline

4. 4

   Lai C-L, Dienstag J, Schiff E. Prevalence and clinical correlates of YMDD variants during lamivudine therapy for patients with chronic hepatitis B. Clin Infect Dis 2003;36:687-696
   CrossRef | Web of Science | Medline