Correspondence

Peginterferon and Lamivudine for Hepatitis B

N Engl J Med 2004; 351:2879December 30, 2004

Article

To the Editor:

Marcellin and colleagues (Sept. 16 issue)1 report that patients with hepatitis B e antigen (HBeAg)–negative chronic hepatitis B had higher rates of a sustained response to treatment with peginterferon alfa-2a than with lamivudine.1 HBeAg-negative chronic hepatitis B is usually associated with precore mutations,2 but it may also develop in patients infected with wild-type strains, with mutations in the basic core promoter.3 Whether these two groups of patients with HBeAg-negative chronic hepatitis differ in their responses to therapy is not known. The study by Marcellin et al. would have been more informative if hepatitis B virus (HBV) genome sequencing and genotyping had been performed in all the patients.

Marcellin and colleagues also report that a more profound suppression of HBV DNA, as seen with combination therapy, led to a lower incidence of lamivudine resistance. We suggest an alternative explanation for this finding. Interferon may allow the immune response to clear infected hepatocytes by restoring T-cell reactivity more efficiently and more durably than lamivudine.4 Whether this CD4-mediated response to HBV antigens occurred concomitantly with a rapid decline of viremia has yet to be determined.

N. Nimer Assy, M.D.
Osamah Hussein, M.D.
Sieff Hospital, Safed 13100, Israel
assy.n@ziv.health.gov.il

4 References

1. 1

   Marcellin P, Lau GKK, Bonino F, et al. Peginterferon alfa-2a alone, lamivudine alone, and the two in combination in patients with HBeAg-negative chronic hepatitis B. N Engl J Med 2004;351:1206-1217
   Full Text | Web of Science | Medline

2. 2

   Carman WF, Jacyna MR, Hadziyannis S, McGarvey M, Karayiannis P, Thomas HC. Mutation preventing formation of hepatitis B e antigen in patients with chronic hepatitis B infection. Lancet 1989;2:588-591
   CrossRef | Web of Science | Medline

3. 3

   Lindh M, Horal P, Dhillon AP, Furuta Y, Norkrans G. Hepatitis B virus carriers without precore mutations in hepatitis B e antigen-negative stage show more severe liver damage. Hepatology 1996;24:494-501
   CrossRef | Web of Science | Medline

4. 4

   Boni C, Bertoletti A, Penna A, et al. Lamivudine treatment can restore T cell responsiveness in chronic hepatitis B. J Clin Invest 1998;102:968-975
   CrossRef | Web of Science | Medline

Author/Editor Response

HBV genome sequencing and genotyping were performed in the majority of the patients in our study (>94 percent), and baseline data have been presented elsewhere.1 Data on treatment responses stratified according to the presence or absence of mutations in the precore or basic core promoter cannot be discussed in detail in the context of this reply. However, univariate and multivariate analyses that included all treated patients showed that the presence or absence of such mutations was not significantly associated with a sustained response. Data on the effect of the HBV genotype are too complex to do justice to them in this reply, but some of our findings, including the potential benefit of combination therapy with peginterferon alfa-2a plus lamivudine in patients with genotype D, have recently been reported.2

The exact mechanism that leads to a reduced incidence of lamivudine resistance in the combination-therapy group is not known, although we discuss some of the theories in our report. Assy and Hussein's theory regarding the enhanced restoration of CD4-mediated responses with peginterferon alfa-2a is interesting. However, T-cell activity in response to peginterferon alfa-2a, with or without lamivudine, was not analyzed in our study.

Patrick Marcellin, M.D.
Hôpital Beaujon, 92110 Clichy, France
patrick.marcellin@bjn.ap-hop-paris.fr

for the Peginterferon Alfa-2a HBeAg-Negative Chronic Hepatitis B Study Group

2 References

1. 1

   Marcellin P, Lau GKK, Bonino F, et al. A Phase III, partially double-blinded study evaluating the efficacy and safety of peginterferon alfa-2a (40KD) (PEGASYS) alone or in combination with lamivudine vs lamivudine in 546 patients with HBeAg-negative/anti-HBe-positive chronic hepatitis B. Hepatology 2003;38:Suppl 1:724A-725A abstract.
   CrossRef | Web of Science

2. 2

   Bonino F, Lau G, Marcellin P, et al. The first detailed analysis of predictors of response in HBeAg-negative chronic hepatitis B: data from a multicenter, randomized, partially double-blind study of peginterferon alfa-2a (40KD) (PEGASYS) alone or in combination with lamivudine vs lamivudine alone. Hepatology 2004;40:Suppl 1:659A-659A abstract.
   Web of Science