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Pegylated Interferon-[Alpha]2b and Lamivudine in Hepatitis B E Antigen-Positive Chronic Hepatitis B/IN RESPONSE

Posted on: Wednesday, 7 September 2005, 03:01 CDT

TO THE EDITOR: In Chan and colleagues' study of pegylated interferon in patients with hepatitis B e antigen (HBeAg)-positive chronic hepatitis B (1), the sustained virologic response (HBeAg seroconversion and hepatitis B virus DNA level less than 500 000 copies/mL) was 36% after 32 weeks of therapy with pegylated interferon-α2b plus 52 weeks of lamivudine. This percentage is comparable with the HBeAg seroconversion rates in 2 global studies investigating combination therapy with pegylated interferon and lamivudine for 1 year (2, 3). In one of these studies, coordinated by our group (2), patients were treated for 52 weeks with pegylated interferon-α2b and lamivudine, and HBeAg seroconversion was achieved in 25% at the end of treatment. In the study by Lau and colleagues (3), patients were treated with pegylated interferon- α2a and lamivudine for 48 weeks and 24% experienced HBeAg seroconversion at the end of treatment.

The 60% HBeAg seroconversion at the end of treatment in the study by Chan and colleagues is very high compared with previous studies, particularly considering the high prevalence of genotype C in their patients, which is probably associated with a less favorable outcome (2). Furthermore, for treatment-naive patients, the study by Chan and colleagues shows a very high percentage of lamivudine resistance (40%) in the lamivudine monotherapy group as determined by the INNO- LiPA assay (Innogenetics N.V., Ghent, Belgium). In the combination therapy group, the rate of lamivudine resistance was 21%. The lamivudine resistance rate in our study was only 11% in the combination therapy group as determined by the same assay. It is tempting to speculate that some of Chan and colleagues' patients were previously exposed to lamivudine therapy. We wonder whether the authors can explain the high end-of-treatment response and the high incidence of YMDD mutants.

Martijn J. ter Borg, MD

Harry L.A. Janssen, MD, PhD

Erasmus Medical Center Rotterdam

3015 GD Rotterdam, the Netherlands

Potential Financial Conflicts of Interest: None disclosed.

References

1. Chan HL, Leung NW, Hui AY, Wong VW, Liew CT, CWm AM, et al. A randomized, controlled trial of combination therapy for chronic hepatitis B: comparing pegylated interferon-alpha2b and lamivudine with lamivudine alone. Ann Intern Med. 2005;142:240-50. [PMID: 15710957]

2. Janssen HL, van Zonneveld M, Senturk H, Zeuzem S, Akarca US, Cakaloglu Y, et al. Pegylated interferon alfa-2b alone or in combination with lamivudine for HBeAg-positive chronic hepatitis B: a randomised trial. Lancet. 2005;365:123-9. [PMID: 15639293]

3. Lau GK, Piratvisuth T, Luo KX, Marcellin P, Thongsawat S, Cooksley G, et al. Peginterferon alfa-2a, lamivudine, and the combination for HBeAg-positive chronic hepatitis B. N Engl J Med. 2005;352:2682-95. [PMID: 15987917]

IN RESPONSE: We appreciate the interest and comments of Drs. ter Borg and Janssen. In our study, the proportion of patients who achieved HBeAg seroconversion at the end of combination treatment with pegylated interferon and lamivudine (60%) was indeed substantially higher than that reported in 2 other multicenter studies (25% to 27%) (1,2). We agree that this result is surprising, since pegylated interferon was given for 32 weeks in our study compared with a longer treatment duration (48 to 52 weeks) in the other 2 studies. We started pegylated interferon-α2b 8 weeks before the commencement of lamivudine treatment, in contrast to the other studies, which administered the drugs simultaneously. We hypothesize that our staggered administration of an immunomodulator followed by lamivudine might have allowed maximal host immune stimulation by pegylated interferon because reduction of viral load by coadministration of an antivital agent would have been avoided. This hypothesis, however, requires confirmation by future viral kinetics studies using different regimens of combination therapy. We suspect that the inclusion of a significant proportion of patients with previous interferon or lamivudine treatment failure in the 2 multicenter studies might have affected the overall treatment response (1, 2). Hepatitis B virus genotype may not be important in our study because it was not found to influence the sustained virologie response in our patients up to 3 years after treatment (3).

We concur with Drs. ter Borg and Janssen that the rate of lamivudine resistance was high in our report. We did extensive interviews and medical record searches to exclude previous use of lamivudine when we recruited patients. Because lamivudine was registered in Hong Kong in 1999, the year we started our study, a hidden but significant previous exposure to lamivudine seemed extremely unlikely. The rate of lamivudine resistance among patients treated with lamivudine monotherapy in our study (40%) was comparable to that reported by Lau and colleagues (34%) (2). The higher rate of lamivudine resistance as compared with previous early reports may be related to the higher sensitivity of the laboratory tool we use today. We are not certain why our patients receiving combination treatment have a higher incidence of lamivudine- resistant mutations (21%) than in the other 2 studies (11%). The relatively small number of patients in our study may have biased the results. Whether patient ethnicity or viral genotype plays a role will require further investigation.

Henry L. Y. Chan, MD

Joseph J.Y. Sung, MD, PhD

The Chinese University of Hong Kong

Shatin, Hong Kong, China

Potential Financial Conflicts of Interest: None disclosed.

References

1. Janssen HL, van Zonneveld M, Senturk H, Zeuzem S, Akarca US, Cakaloglu Y, et al. Pegylated interferon alfa-2b alone or in combination with lamivudine for HBeAg-positive chronic hepatitis B: a randomised trial. Lancet. 2005;365:123-9. [PMID: 15639293]

2. Lau GK, Pirarvisuth T, Luo KX, Marcellin P, Thongsawat S, Cooksley G, et al. Peginterferon alfa-2a, lamivudine, and the combination for HBeAg-positive chronic hepatitis B. N Engl J Med. 2005;352:2682-95. [PMID: 15987917]

3. Chan HL, Hui AY, Wong VW, Chim AM, Wong ML, Sung JJ. Long- term follow-up of peginterferon and lamivudine combination treatment in HBeAg-positive chronic hepatitis B. Hepatology. 2005;41:1357-64. [PMID: 15880608]

Copyright American College of Physicians Sep 6, 2005

Source: Annals of Internal Medicine

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