Henry Lik-Yuen Chan, MD; Nancy Wai-Yee Leung, MD; Alex Yui Hui, MB, BChir; Vincent Wai-Sun Wong, MBChB; Choong-Tsek Liew, MD; Angel Mei-Ling Chim, BSc; Francis Ka-Leung Chan, MD; Lawrence Cheung-Tsui Hung, MB, BChir; Yuk-Tong Lee, MD; John Siu-Lun Tam, PhD; Christopher Wai-Kei Lam, PhD; Joseph Jao-Yiu Sung, MD, PhD
Grant Support: Schering-Plough Corp. supplied pegylated interferon-α2b, and GlaxoSmithKline supplied lamivudine.
Potential Financial Conflicts of Interest: None disclosed.
Requests for Single Reprints: Joseph J.-Y. Sung, MD, PhD, Department of Medicine and Therapeutics, 9/F Prince of Wales Hospital, 30–32 Ngan Shing Street, Shatin, Hong Kong SAR, China; e-mail, email@example.com.
Current Authors Addresses: Drs. H.L.-Y. Chan, F.K.-L. Chan, Lee, and Sung; Mr. Hui; Mr. Wong; Ms. Chim; and Mr. Hung: Departments of Medicine and Therapeutics, 9/F Prince of Wales Hospital, 30–32 Ngan Shing Street, Shatin, Hong Kong SAR, China.
Dr. Leung: Department of Medicine, Alice Ho Miu Ling Nethersole Hospital, 11 Chuen On Road, Tai Po, Hong Kong SAR, Hong Kong.
Dr. Liew: Department of Anatomical and Cellular Pathology, 1/F Prince of Wales Hospital, 30–32 Ngan Shing Street, Shatin, Hong Kong SAR, China.
Dr. Tam: Department of Microbiology, 1/F Prince of Wales Hospital, 30–32 Ngan Shing Street, Shatin, Hong Kong SAR, China.
Dr. Lam: Department of Chemical Pathology, 1/F Prince of Wales Hospital, 30–32 Ngan Shing Street, Shatin, Hong Kong SAR, China.
Author Contributions: Conception and design: H.L.-Y. Chan, J.J.-Y. Sung.
Analysis and interpretation of the data: H.L.-Y. Chan, J.J.-Y. Sung.
Drafting of the article: H.L.-Y. Chan.
Critical revision of the article for important intellectual content: H.L.-Y. Chan, J.J.-Y. Sung.
Final approval of the article: H.L.-Y. Chan, J.J.-Y. Sung.
Provision of study materials or patients: H.L.-Y. Chan, N.W.-Y. Leung, A.Y. Hui, V.W.-S. Wong, F.K.-L. Chan, L.C.-T. Hung, Y.-T. Lee.
Statistical expertise: H.L.-Y. Chan.
Obtaining of funding: C.-T. Liew, J.J.-Y. Sung.
Administrative, technical, or logistic support: A.M.-L. Chim, J.S.-L. Tam, C.W.-K. Lam, J.J.-Y. Sung.
Collection and assembly of data: A.M.-L. Chim.
Chan H., Leung N., Hui A., Wong V., Liew C., Chim A., Chan F., Hung L., Lee Y., Tam J., Lam C., Sung J.; A Randomized, Controlled Trial of Combination Therapy for Chronic Hepatitis B: Comparing Pegylated Interferon-α2b and Lamivudine with Lamivudine Alone. Ann Intern Med. 2005;142:240-250. doi: 10.7326/0003-4819-142-4-200502150-00006
Download citation file:
Published: Ann Intern Med. 2005;142(4):240-250.
Few studies have evaluated combination therapies for chronic hepatitis B.
In this single-center, open-label trial, 100 patients with hepatitis B e antigen–positive chronic hepatitis B and moderately elevated alanine aminotransferase levels were randomly assigned to a staggered regimen of pegylated interferon-α2b for 32 weeks plus lamivudine for 52 weeks or lamivudine monotherapy. Patients receiving combination therapy more often had virologic responses and less often developed lamivudine-resistant mutants than those receiving monotherapy. Transient influenza-like symptoms, alopecia, and local erythematous reactions were more common with combination therapy.
Patients assigned to combination therapy received treatment for 8 weeks longer than those assigned to monotherapy.
Martijn J. ter Borg
Erasmus Medical Center Rotterdam
March 13, 2005
Pegylated Interferon-alfa2b and lamivudine in HBeAg-positive chronic hepatitis B
TO THE EDITOR: With great interest we read the article by Chan and colleagues on the treatment with pegylated interferon of HBeAg-positive chronic hepatitis B (1). In this study, they found after 32 weeks of pegylated interferon-alfa2b combined with 52 weeks of lamivudine an end of follow-up response (HBeAg seroconversion and HBV DNA level less than 500.000 copies/ml) of 36%. This percentage is comparable with the HBeAg- seroconversion rates of two global studies investigating combination therapy of 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-alfa2b and lamivudine, and HBeAg-seroconversion was achieved in 25% at the end of treatment. In the study from Lau and colleagues (3), patients were treated with pegylated interferon-alfa-2a and lamivudine for 48 weeks and 24% of the patients had an HBeAg-seroconversion at the end of treatment. The 60% HBeAg- seroconversion at the end of treatment in the study by Chan et al. is very high compared to the previous studies, particularly taken into account the high prevalence of genotype C in this study, which is probably associated with a less favorable outcome (2).
Furthermore, for treatment-naÃ¯ve patients, the study by Chan et al. shows a very high percentage of lamivudine resistance (40%) in the lamivudine monotherapy group as determined by the INNO-LiPA assay. In the combination therapy group this was 21%. In our study the lamivudine resistance rate was only 11% in the combination therapy group being determined by the same assay. It is tempting to speculate that some patients in the population studied by Chan et al. did have previous exposure to lamivudine therapy. We wonder whether the authors have an explanation for the high end of treatment response and for the high incidence of YMDD mutants.
Martijn J. ter Borg, MD Harry L.A. Janssen, MD
Dept. of Gastroenterology and Hepatology Erasmus Medical Center Rotterdam Dr. Molewaterplein 40 3015 GD Rotterdam The Netherlands
1. Chan HL, Leung NW, Hui AY, 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(4):240-50.
2. Janssen HL, van Zonneveld M, Senturk H, et al. Pegylated interferon alfa-2b alone or in combination with lamivudine for HBeAg- positive chronic hepatitis B: a randomised trial. Lancet. 2005;365(9454):123-9.
3. Lau G, Pivatvisuth T, Luo K, et al. Peginterferon alfa-2a (40KD) monotherapy and in combination with lamivudine more effective than lamivudine monotherapy in HBeAg-positive chronic hepatitis B: results from a large, multinational study. Hepatology. 2004;40(4, suppl. 1):171A.
Joseph JY Sung
Department of Medicine and Therapeutics, The Chinese University of Hong Kong
April 14, 2005
Pegylated interferon alfa-2b and lamivudine in HBeAg positive chronic hepatitis B
We appreciate the interest and comments of Dr. Dr. Janssen to our work. In our study, the proportion of patients who achieved HBeAg seroconversion at the end of combination pegylated interferon and lamivudine treatment (60%) was indeed substantially higher than that reported in 2 other multi-centered studies (25%-27%) [1,2,3]. We agree this result is surprising as peginterferon was given for 32 weeks in our study as compared to the longer (48-52 weeks) treatment duration in the other 2 studies. We started pegylated interferon alfa-2b 8 weeks prior to the commencement of lamivudine treatment as in contrast to the simultaneously administration of the drugs in other studies. We hypothesize that our staggered administration of immuno-modulator followed by lamivudine might allow maximal host immune stimulation by peginterferon as it avoids reduction of viral load by co-administration of anti-viral agent. This hypothesis however requires confirmation by future viral kinetics studies using different regimens of combination therapy. We suspect the inclusion of a significant proportion of patients who failed interferon and/or lamivudine treatment in the 2 multi-centered studies might affect their overall treatment response [2,3]. HBV genotype may not be important here as it was not found to influence the sustained virological response after we have followed up these patients for up to 3 years post-treatment .
We concur with Dr. Janssen that the rate of lamivudine resistance was high in our report. We have performed very extensive interview and medical record search to exclude previous usage of lamivudine on patient recruitment. As lamivudine was registered in Hong Kong in 1999, which coincided with 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%) . The higher rate of lamivudine resistance as compared to previous early reports may be related to the higher sensitivity of the laboratory tool we use nowadays. We are not certain why our patients on combination treatment have a higher incidence of lamivudine resistant mutations (21%) as compared to the other 2 studies (11%). The relatively small number of patients in our study may impose some bias to the results. Whether patient ethnicity or viral genotype plays a role will require further investigations.
1. Chan HLY, Leung NWY, Hui, AY, et al. A randomized, controlled trial of combination therapy for chronic hepatitis B: Comparing pegylated interferon-alfa-2b and lamivudine with lamivudine alone. Ann Intern Med 2005;142:240-50.
2. Janssen HLA, van Zonneveld M, Senturk H, et al. Pegylated interferon alfa-2b along or in combination with lamivudine for HBeAg- positive chronic hepatitis B: a randomised trial. Lancet 2005;365:123-9.
3. Lau G, Pivatvisuth T, Luo K, et al. Peginterferon alfa-2a (40KD) monotherapy and in combination with lamivudine is more effective than lamivudine monotherapy in HBeAg-positive chronic hepatitis B : results from a large, multinational study. Hepatology 2004;40 supp 1:171A.
4. Chan HLY, Hui AY, Wong VWS, et al. Long-term follow-up of peginterferon and lamivudine combination treatment in HBeAg-positive chronic hepatitis B. Hepatology (in press).
to gain full access to the content and tools.
Learn more about subscription options.
Register Now for a free account.
Gastroenterology/Hepatology, Infectious Disease, Liver Disease, Prevention/Screening.
Results provided by:
Copyright © 2016 American College of Physicians. All Rights Reserved.
Print ISSN: 0003-4819 | Online ISSN: 1539-3704
Conditions of Use
This PDF is available to Subscribers Only