Treatment of Hepatitis B e Antigen-Positive Chronic Hepatitis with Telbivudine or Adefovir: A Randomized Trial

4 December 2007 | Volume 147 Issue 11

Background: The efficacy of nucleoside and nucleotide analogues for hepatitis B has been linked to the magnitude and durability of hepatitis B virus (HBV) suppression.

Objective: To compare the antiviral efficacy of telbivudine and adefovir dipivoxil, and the effects of switching from adefovir to telbivudine, in hepatitis B e antigen (HBeAg)–positive patients with chronic hepatitis B.

Design: Randomized, controlled, open-label trial.

Setting: 16 outpatient clinics.

Patients: 135 treatment-naive, HBeAg-positive adults with chronic hepatitis B.

Intervention: Patients were randomly assigned in a 1:1:1 ratio to telbivudine (group A), adefovir (group B), or 24 weeks of adefovir and then telbivudine for the remaining 28 weeks (group C). One hundred thirty-one patients completed 52 weeks of treatment.

Measurements: The primary efficacy comparison was serum HBV DNA reduction at week 24, with a secondary comparison at week 52.

Results: At week 24, mean HBV DNA reduction was greater in group A than in pooled groups B and C (–6.30 vs. –4.97 log₁₀ copies/mL; difference, –1.33 log₁₀ copies/mL [95% CI, –1.99 to –0.66 log₁₀ copies/mL]; P < 0.001), and more patients in group A were polymerase chain reaction–negative (39% vs. 12%; odds ratio, 4.46 [CI, 1.86 to 10.72]; P = 0.001). At week 52, mean residual HBV DNA was lower in patients treated continuously with (group A) or switched (group C) to telbivudine than in those who received continuous adefovir (group B) (3.01 log₁₀ copies/mL [group A] and 3.02 log₁₀ copies/mL [group C] vs. 4.00 log₁₀ copies/mL [group B]; difference, –0.99 log₁₀ copies/mL [CI, –1.67 to –0.32 log₁₀ copies/mL] and –0.98 log₁₀ copies/mL [CI, –1.64 to –0.32 log₁₀ copies/mL]; P = 0.004). Adverse events were similar across groups; the most common were upper respiratory symptoms, headache, back pain, and diarrhea.

Limitations: The trial was open-label and was not of sufficient size or duration to compare clinical outcomes and long-term efficacy.

Conclusions: Telbivudine demonstrated greater and more consistent HBV DNA suppression than adefovir after 24 weeks of treatment. After 52 weeks, HBV DNA suppression was greater in patients who had received continuous telbivudine or were switched to telbivudine after 24 weeks than in those who received continuous adefovir.

*For members of the 018 Study Group, see the Appendix.

ClinicalTrials.gov registration number: NCT00115245.

Editors' Notes Context Optimal regimens for suppressing virus in chronic hepatitis B infections are unclear. Contribution In this 52-week open label trial, 135 adults with hepatitis e antigen positive chronic hepatitis B were randomly assigned to telbuvidine, adefovir, or adefovir for 24 weeks followed by telbivudine for 28 weeks. The telbivudine and the adefovir to telbivudine groups experienced similar reductions in viral levels that were greater than those in the adefovir group. Cautions The small trial did not establish long-term drug resistance or effects on clinical outcomes. Implications Telbivudine and switching from adefovir to telbivudine suppressed viral levels more than adefovir in adults with chronic hepatitis B. —The Editors

 

Author and Article Information

From The Chinese University of Hong Kong, Hong Kong, China; University of Toronto, Toronto, Ontario, Canada; Hôpital Beaujon, Clichy, France; Pusan National University Hospital, Busan, Korea; Severance Hospital, Seoul, Korea; Tri-Service General Hospital, Taipei, Taiwan; University of Calgary, Calgary, Alberta, Canada; University of Manitoba, Winnipeg, Manitoba, Canada; University of Miami, Miami, Florida; Monash University, Melbourne, Victoria, Australia; California Pacific Medical Center, San Francisco, California; Novartis Pharmaceuticals, East Hanover, New Jersey; and Idenix Pharmaceuticals, Cambridge, Massachusetts.

Acknowledgments: The authors thank Drs. Raymond Koff and Richard Boehme for their assistance in the preparation of this manuscript.

Potential Financial Conflicts of Interest: Employment: G. Harb (Novartis), R. Kaiser (Idenix), X.-J. Qiao (Idenix). Consultancies: P. Marcellin (Idenix, Novartis, Roche, Bristol-Meyers Squibb, Gilead), C.-L. Lai (Idenix, Novirio Pharmaceuticals), G.Y. Minuk (Novartis Canada, Bristol-Meyers Squibb Canada). Honoraria: P. Marcellin (Idenix, Novartis, Roche, Bristol-Meyers Squibb, Gilead), C.-L. Lai (Idenix, Novartis). Stock ownership or options (other than mutual funds): R. Kaiser (Idenix), X.-J. Qiao (Idenix). Expert testimony: E.J. Heathcote (Canadian Health Protection Board). Grants received: C.-L. Lai (Idenix, Novartis), M. Cho (Quintiles East Asia), N. Bzowej (Idenix, Roche, Vertex, Schering, GlaxoSmithKline, Bristol-Meyers Squibb, Gilead, Wyeth, Human Genome Sciences, Celera Diagnostics). Grants pending: M. Cho (Quintiles East Asia).

Reproducible Research Statement: A synopsis of the protocol is available to interested readers by contacting 877-889-9352. Statistical code and data are not available.

Requests for Single Reprints: Dr. Henry LY Chan, The Chinese University of Hong Kong, 9/F Prince of Wales Hospital, Shatin, Hong Kong, China; e-mail, hlychan{at}cuhk.edu.hk.

Current Author Addresses: Dr. Chan: The Chinese University of Hong Kong, 9/F Prince of Wales Hospital, Shatin, Hong Kong, China.

Dr. Heathcote: Toronto Western Hospital, 399 Bathurst Street, Toronto, Ontario, Canada M5T 2S8.

Dr. Marcellin: Hôpital Beaujon, 100 Bld Général Leclerc, 92110 Clichy, France.

Dr. Lai: Department of Medicine, University of Hong Kong, 102 Pokfulam Road, Hong Kong, China.

Dr. Cho: Pusan National University Hospital, 1-10 Ami-dong Seo-gu, Busan, Korea, 602-739.

Dr. Moon: Yonsei University College of Medicine, 134 Shinchon-Dong, Seodaemun-Ku, Seoul, South Korea, 120-752.

Dr. Chao: Tri-Service General Hospital, Number 325, Sec. 2, Cheng-Kung Road, Taipei, Taiwan,114.

Dr. Myers: Health Sciences Centre, University of Calgary, 3330 Hospital Drive NW, Calgary, Alberty, Canada, T2N 4N1.

Dr. Minuk: University of Manitoba, 703 McDermot Avenue, Winnipeg, Manitoba, Canada, R3E 3P4.

Dr. Jeffers: University of Miami Center for Liver Diseases, 1500 NW 12th Avenue 1101, Miami, Florida 33136.

Dr. Sievert: Monash Medical Center, Monash University, 246 Clayton Road, Melbourne, Victoria, 3165, Australia.

Dr. Bzowej: California Pacific Medical Center, 2340 Clay Street, San Francisco, California 94115.

Dr. Harb: Novartis, 1 Health Plaza, East Hanover, New Jersey 07936.

Drs. Kaiser, Qiao, and Brown: Idenix Pharmaceuticals, 1 Kendall Square, Cambridge, Massachusetts 02139.

Author Contributions: Conception and design: H.L.Y. Chan, C.-L. Lai, M. Cho, G. Harb, N.A. Brown.

Analysis and interpretation of the data: H.L.Y. Chan, E.J. Heathcote, P. Marcellin, C.-L. Lai, M. Cho, R.P. Myers, G.Y. Minuk, W. Sievert, G. Harb, N.A. Brown.

Drafting of the article: H.L.Y. Chan, P. Marcellin, C.-L. Lai, M. Cho, W. Sievert, G. Harb, N.A. Brown.

Critical revision of the article for important intellectual content: H.L.Y. Chan, E.J. Heathcote, P. Marcellin, C.-L. Lai, M. Cho, R.P. Myers, G.Y. Minuk, L. Jeffers, W. Sievert, N. Bzowej, N.A. Brown.

Final approval of the article: H.L.Y. Chan, E.J. Heathcote, P. Marcellin, C.-L. Lai, M. Cho, R.P. Myers, G.Y. Minuk, W. Sievert, N. Bzowej, G. Harb, N.A. Brown.

Provision of study materials or patients: H.L.Y. Chan, E.J. Heathcote, P. Marcellin, C.-L. Lai, M. Cho, Y.-C. Chao, R.P. Myers, G.Y. Minuk, W. Sievert, N. Bzowej.

Statistical expertise: X.-J. Qiao.

Administrative, technical, or logistic support: R. Kaiser, N.A. Brown.

Collection and assembly of data: G.Y. Minuk, N. Bzowej, N.A. Brown.