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How Long Do Chronic Hepatitis B Patients Need to be Treated to Sustain HBeAg Seroconversion?

SUMMARY: Longer treatment with antiviral agents such as lamivudine, and use of pegylated interferon for selected individuals, increases the likelihood of sustained hepatitis B "e" antigen (HBeAg) seroconversion and viral suppression in people with chronic hepatitis B, according to a set of recently published reports. Across the studies, younger age and longer duration of lamivudine therapy predicted sustained response. The data were not entirely consistent, however, indicating the need for further research in this area.

By Liz Highleyman

Virological response, or undetectable hepatitis B virus (HBV) viral load, is one measure of successful treatment. But chronic hepatitis B patients ideally will also achieve success by other measures, including biochemical response (alanine aminotransferase [ALT] normalization) and serological response, or HBeAg seroconversion (loss of "e" antigen and production of "e" antibodies). The type and duration of treatment that best promotes HBeAg seroconversion is not fully understood, however.


As described in the April 7, 2010 advance online edition of Gastroenterology, Jurrien Reijnders and colleagues from the Netherlands and China studied the long-term durability of HBeAg seroconversion in 132 chronic hepatitis B patients treated with nucleoside/nucleotide analogs such as lamivudine (Epivir-HBV). During a median treatment duration of 26 months, 46 participants (35%) experienced HBeAg seroconversion. Out of this group, 42 continued follow-up after seroconversion, and a subset of 33 (79%) stayed on treatment.

About one-third of the continuing participants (13 out of 42, or 31%) showed durable response, defined as HBeAg negative and HBV DNA < 10,000 copies/mL, over a median follow-up period of 59 months. However, among the patients who continued treatment, 22 (67%) experienced serological or virological relapse, usually preceded by the development of drug resistance in people using lamivudine monotherapy. Among the 9 patients who discontinued treatment 6 months or more after HBeAg seroconversion, only 2 sustained a durable response in the absence of therapy.

"Induction of HBeAg seroconversion by nucleos(t)ide analogues is temporary in most patients with chronic HBV infection," the study authors concluded. "Long-term continuation of nucleos(t)ide analogue treatment, irrespective of the occurrence of HBeAg seroconversion, appears to be necessary."

Hyun Woong Lee and colleagues from Korea also looked at the likelihood and predictors of sustained HBeAg seroconversion, as reported in the February 2010 issue of Hepatology. Between January 1999 and August 2004, 178 Korean HBeAg positive chronic hepatitis B patients were treated with lamivudine monotherapy for an average duration of 26 months and achieved complete response, defined as serum HBeAg loss, undetectable HBV DNA, and ALT normalization.

Among this group, 138 participants (78%) achieved sustained virological response, or SVR, while 40 experienced viral rebound. Cumulative relapse rates increased from 16% after 1 year to 30% after 5 years. The mean time to relapse after stopping lamivudine was 12 months, and most relapses (83%) occurred within 2 years after discontinuation. In a multivariate analysis, patients who were age 40 or younger and those treated for more than 12 months after HBeAg loss or seroconversion were more likely to achieve SVR. "Age and additional treatment were major predictive factors for SVR," the investigators concluded.

Yuan-Hung Kuo and colleagues from Taiwan likewise assessed post-treatment durability of HBeAg seroconversion and optimal length of lamivudine therapy needed to maintain seroconversion (January 2010 Scandinavian Journal of Gastroenterology). This retrospective analysis included 401 treatment-naive HBeAg positive chronic hepatitis B patients treated with lamivudine for at least 24 weeks (range 24-258 weeks). Within this group, 124 participants who achieved complete response at the end of treatment (again, HBeAg seroconversion, undetectable HBV DNA, and ALT normalization) were followed for at least 48 weeks.

One-third of the complete responders (42 out of 124, or 34%) achieved sustained response lasting at least 48 weeks. But a majority relapsed, with cumulative relapse rates of 54% after 1 year and 68% after 2 years. This study found that an age of 34 or younger and treatment for more than 2 years were independent predictors of sustained response. "Lamivudine-induced HBeAg seroconversion is not durable in Taiwan," the researchers concluded. "However, a duration of lamivudine consolidation therapy > 48 weeks may be favorable for maintaining durable HBeAg seroconversion."

In another related study, published in the April 2010 Journal of Viral Hepatitis, L. Wang and colleagues conducted a long-term follow-up study of 125 Chinese HBeAg positive chronic hepatitis B patients treated with lamivudine using stringent cessation criteria. Here, 82 people (65%) achieved HBeAg seroconversion, with the rest experiencing HBeAg loss, and all achieved undetectable HBV DNA during treatment. Participants continued lamivudine for at least 6 months after HBeAg loss (median 36 months) or seroconversion (median 24 months).

Among patients who achieved HBeAg seroconversion, cumulative viral relapse rates were 23% after 1 year, 25% after 2 years, 25% after 3 years, and 29% after 4 years. Among those treated for 18 months or more, viral relapse rates were significantly lower (18%, 20%, 20%, and 25%, respectively). Relapsers were significantly older than non-relapsers on average (34 vs 23 years). Over 5 years, participants younger than 30 years had a relapse rate of just 12%, compared with 53% among older patients.

The Chinese investigators concluded that, "for patients who maintained HBeAg seroconversion for >6 months and total duration for >18 months, lamivudine withdrawal is a reasonable option." However, they continued, "Prolonged treatment may be required for patients aged greater than 30 years to reduce relapse."


In addition to nucleoside/nucleotide analogs, pegylated interferon monotherapy are also approved for treatment of chronic hepatitis B. People treated with lamivudine and those treated with pegylated interferon have a similar likelihood of achieving HBeAg seroconversion 6 months after the end of treatment -- about 30%-40% -- but is response sustained for equal duration?

As described in the April 2010 issue of Hepatology, Vincent Wai-Sun Wong and colleagues from Hong Kong analyzed 85 HBeAg positive hepatitis B patients who received pegylated interferon alfa-2b (PegIntron) for 32 weeks and lamivudine for 52 or 104 weeks. Follow-up continued for an average of 6 years.

Nearly one-third of participants (29%) showed both sustained HBeAg seroconversion and undetectable HBV DNA at 5 years. The seroconversion rate rose progressively from 37% at the end of treatment to 60% at 5 years. Virological response rates were lower, 32% at the end of pegylated interferon treatment and at 13% at 5 years. Among patients who were responders at the end of treatment, 82% showed sustained HBeAg seroconversion and 57% had sustained viral suppression at 5 years.

Viral load at week 16, end-of-treatment HBeAg seroconversion, and end-of-treatment undetectable HBV DNA were independent predictors of response at 5 years. But in contrast with the studies above, when combined with pegylated interferon the duration of lamivudine had no effect on long-term response.

Expert Recommendations

Finally, a report in the March 18, 2010 advance online edition of Digestive Diseases and Sciences presented conclusions from a 2-day meeting of leading hepatologists with extensive experience managing chronic hepatitis B patients in the Asia-Pacific region. The meeting was held to review and evaluate available data on the relationship between HBeAg seroconversion and clinical outcomes, as well as how seroconversion should influence patient management.

The experts agreed that HBeAg seroconversion is "an important serologic end point for patients with chronic hepatitis B and that achieving this goal should be an important consideration in treatment selection."

With regard to type of treatment, they concluded, "Patients with HBeAg positive chronic hepatitis B should consider pegylated interferon if they are aged < 40 years (especially women), have lower HBV DNA levels, can afford this treatment, and have a lifestyle that would support adherence to injection therapy."

Alternatively, they continued, "nucleos(t)ide analogs are recommended in patients with alanine aminotransferase levels >2 x the upper limit of normal, HBV DNA levels < 9 log(10) IU/mL, and compensated chronic hepatitis B.

Lamivudine is an older antiviral drug that has a relatively low barrier to resistance. Instead, the hepatologists recommended that 3 newer drugs -- entecavir (Baraclude), telbivudine (Tyzeka), and tenofovir (Viread) -- may be used as first-line therapy. "[T]hey can be administered as a finite therapeutic course in HBeAg positive patients who seroconvert," they stated. "Telbivudine and tenofovir should be considered in women of child-bearing potential."

Investigator affiliations:

Reijnders study: Department of Gastroenterology & Hepatology and Department of Epidemiology & Biostatistics, Erasmus MC University Medical Center Rotterdam, Rotterdam, Netherlands; Department of Gastroenterology, Zong Shan Hospital, Fudan University, Shanghai, China.

Lee study: Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea; Department of Internal Medicine, Chung-Ang University College of Medicine, Seoul, Korea; Liver Cirrhosis Clinical Research Center, Seoul, Korea; Department of Internal Medicine, Yeungnam University College of Medicine, Seoul, Korea; Department of Internal Medicine, Keimyung University School of Medicine, Seoul, Korea; Department of Internal Medicine, Hanyang University College of Medicine, Seoul, Korea; Department of Internal Medicine, Soonchunhyang University Hospital, Seoul, Korea; Department of Internal Medicine, Kwandong University College of Medicine, Seoul, Korea; Department of Internal Medicine, Yonsei Institute of Gastroenterology, Seoul, Korea; Department of Internal Medicine, National Health Institute Corporation Ilsan Hospital, Seoul, Korea.
Kuo study: Division of Hepato-Gastroenterology, Department of Internal Medicine, Memorial Hospital-Kaohsiung Medical Center, Chang Gung University College of Medicine, Niao-Sung, Taiwan.

Wang study: Department of Infectious Diseases and Hepatology, Second Hospital of Shandong University, Shandong University, Jinan, China; Department of Infectious Disease, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Yantai Infectious Disease Hospital, Yantai, China; Jinan Infectious Disease Hospital, Jinan, China.

Wong study: Department of Medicine and Therapeutics, Chinese University of Hong Kong, Hong Kong.

Liaw report: Liver Research Unit, Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Taipei, Taiwan, Clinical Trial Center, LKS Faculty of Medicine, University of Hong Kong, Humanity and Health GI and Liver Clinic, Hong Kong, SAR, China; Hepatitis Research Center National Taiwan University Hospital, Taipei, Taiwan; New Zealand Liver Transplant Unit, Auckland City Hospital, Auckland, New Zealand.



JG Reijnders, MJ Perquin, N Zhang, and others. Nucleos(t)ide Analogues Only Induce Temporary Hepatitis B e Antigen Seroconversion in Most Patients with Chronic Hepatitis B. Gastroenterology (Abstract). April 7, 2010 (Epub ahead of print).

HW Lee, HJ Lee, JS Hwang, and other. Lamivudine maintenance beyond one year after HBeAg seroconversion is a major factor for sustained virologic response in HBeAg-positive chronic hepatitis B. Hepatology 51(2): 415-421 (Abstract). February 2010.

YH Kuo, CH Chen, JH Wang, and others. Extended lamivudine consolidation therapy in hepatitis B e antigen-positive chronic hepatitis B patients improves sustained hepatitis B e antigen seroconversion. Scandinavian Journal of Gastroenterology
45(1): 75-81 (Abstract). January 2010.

L Wang, F Liu, YD Liu, and others. Stringent cessation criterion results in better durability of lamivudine treatment: a prospective clinical study in hepatitis B e antigen-positive chronic hepatitis B patients. Journal of Viral Hepatitis 17(4): 298-304 (Abstract). April 2010.

VWS Wong, GLH Wong, KKL Yan, and others. Durability of peginterferon alfa-2b treatment at 5 years in patients with hepatitis B e antigen-positive chronic hepatitis B. Hepatology 51(6): 1945-1953 (Abstract). June 2010.

YF Liaw, GK Lau, JH Kao, E Gane. Hepatitis B e Antigen Seroconversion: A Critical Event in Chronic Hepatitis B Virus Infection. Digestive Diseases and Sciences (Abstract). March 18, 2010 (Epub ahead of print).























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