Henry L.Y. Chan, MD; E. Jenny Heathcote, MD; Patrick Marcellin, MD; Ching-Lung Lai, MD; Mong Cho, MD; Young M. Moon, MD; You-Chen Chao, MD; Robert P. Myers, MD; Gerald Y. Minuk, MD; Lennox Jeffers, MD; William Sievert, MD; Natalie Bzowej, MD, PhD; George Harb, MD; Ralf Kaiser, PhD; Xin-Jian Qiao, ScD; Nathaniel A. Brown, MD; and the 018 Study Group (*)
ClinicalTrials.gov registration number: NCT00115245.
Acknowledgment: 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: E.J. Heathcote (Novartis, Gilead Sciences); 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: E.J. Heathcote (Novartis, Gilead Sciences); P. Marcellin (Idenix, Novartis, Roche, Bristol-Meyers Squibb, Gilead), C.L. Lai (Idenix, Novatis). Stock ownership or options (other than mutual funds): R. Kaiser (Idenixs), X.J. Qiao (Idenix). Grants received: E.J. Heathcote (Novartis, Pharmasset, Gilead); 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: Henry L.Y. Chan, MD, The Chinese University of Hong Kong, 9/F Prince of Wales Hospital, Shatin, Hong Kong, China; e-mail, firstname.lastname@example.org.
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 M5T 2S8, Canada.
Dr. Marcellin: Hôpital Beaujon, 100 Boulevard 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, Alberta T2N 4N1, Canada.
Dr. Minuk: University of Manitoba, 715 McDermot Avenue, Winnipeg, Manitoba R3E 3P4, Canada.
Dr. Jeffers: University of Miami Center for Liver Diseases, 1500 NW 12th Avenue 1101, Miami, FL 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, CA 94115.
Dr. Harb: Novartis, 1 Health Plaza, East Hanover, NJ 07936.
Drs. Kaiser, Qiao, and Brown: Idenix Pharmaceuticals, 1 Kendall Square, Cambridge, MA 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, 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.
The efficacy of nucleoside and nucleotide analogues for hepatitis B has been linked to the magnitude and durability of hepatitis B virus (HBV) suppression.
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.
Randomized, controlled, open-label trial.
16 outpatient clinics.
135 treatment-naive, HBeAg-positive adults with chronic hepatitis B.
Patients were randomly assigned in a 1:1:1 ratio to 52 weeks of telbivudine (group A) or 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.
The primary efficacy comparison was serum HBV DNA reduction at week 24, with a secondary comparison at week 52.
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, the mean residual HBV DNA level was lower in group A and group C than in 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.
The trial was open-label and was not of sufficient size or duration to compare clinical outcomes and long-term efficacy.
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.
Optimal regimens for suppressing virus in chronic hepatitis B infection are unclear.
In this 52-week open label trial, 135 adults with hepatitis B 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.
The small trial did not establish long-term drug resistance or effects on clinical outcomes.
Telbivudine and switching from adefovir to telbivudine suppressed viral levels more than adefovir in adults with chronic hepatitis B.
Study flow diagram.
Primary exclusion criteria are listed; some patients met more than 1 exclusion criterion. One patient assigned to adefovir withdrew before initiation of treatment; thus, the intention-to-treat sample was 135 patients, of whom 45, 44, and 46 were assigned to receive telbivudine, adefovir, or adefovir for 24 weeks and then telbivudine for the remaining 28 weeks, respectively. One adefovir recipient withdrew before the week-24 analysis; 1 additional adefovir recipient and 2 telbivudine recipients withdrew before the week-52 analysis. ALT = alanine aminotransferase; HBeAg = hepatitis B e antigen; HBV = hepatitis B virus.
Table 1. Baseline Characteristics
Changes in serum hepatitis B virus (HBV) markers from baseline to week 52.
Top. Mean serum HBV DNA levels. Bottom. Proportion of patients with hepatitis B e antigen (HBeAg) seroconversion. ADV = adefovir; ADV/LdT = adefovir to telbivudine; LdT = telbivudine.
Table 2. Efficacy Results at Week 24 of Treatment
Table 3. Efficacy Results at Week 52 of Treatment
Table 4. Effect of Viral Load at Week 24 on Efficacy Outcomes at Week 52
Table 5. Clinical Adverse Events
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Henry L.Y. Chan, E. Jenny Heathcote, Patrick Marcellin, Ching-Lung Lai, Mong Cho, Young M. Moon, et al. Treatment of Hepatitis B e Antigen–Positive Chronic Hepatitis with Telbivudine or Adefovir: A Randomized Trial. Ann Intern Med. 2007;147:745–754. doi: 10.7326/0003-4819-147-11-200712040-00183
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Published: Ann Intern Med. 2007;147(11):745-754.
Gastroenterology/Hepatology, Infectious Disease, Liver Disease, Viral Hepatitis.
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