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Background Reducing hepatitis B virus (HBV) replication to minimal levels is emerging as a key therapeutic goal for chronic hepatitis B.
Methods In this double-blind, phase 3 trial, 1370 patients with chronic hepatitis B were randomly assigned to receive 600 mg of telbivudine or 100 mg of lamivudine once daily. The primary efficacy end point was noninferiority of telbivudine to lamivudine for therapeutic response (i.e., a reduction in serum HBV DNA levels to fewer than 5 log10 copies per milliliter, along with loss of hepatitis B e antigen [HBeAg] or normalization of alanine aminotransferase levels). Secondary efficacy measures included histologic response, changes in serum HBV DNA levels, and HBeAg responses.
Results At week 52, a significantly higher proportion of HBeAg-positive patients receiving telbivudine than of those receiving lamivudine had a therapeutic response (75.3% vs. 67.0%, P=0.005) or a histologic response (64.7% vs. 56.3%, P=0.01); telbivudine also was not inferior to lamivudine for these end points in HBeAg-negative patients. In HBeAg-positive and HBeAg-negative patients, telbivudine was superior to lamivudine with respect to the mean reduction in the number of copies of HBV DNA from baseline, the proportion of patients with a reduction in HBV DNA to levels undetectable by polymerase-chain-reaction assay, and development of resistance to the drug. Elevated creatine kinase levels were more common in patients who received telbivudine, whereas elevated alanine aminotransferase and aspartate aminotransferase levels were more common in those who received lamivudine.
Conclusions Among patients with HBeAg-positive chronic hepatitis B, the rates of therapeutic and histologic response at 1 year were significantly higher in patients treated with telbivudine than in patients treated with lamivudine. In both the HBeAg-negative and the HBeAg-positive groups, telbivudine demonstrated greater HBV DNA suppression with less resistance than did lamivudine. (ClinicalTrials.gov number, NCT00057265
[ClinicalTrials.gov]
.)
Multiple types of interferon, lamivudine, adefovir dipivoxil, entecavir, and telbivudine have been approved for the treatment of chronic hepatitis B. These agents vary with respect to antiviral and clinical efficacy, resistance profiles, and tolerability and safety.10 For long-term disease management, the clinical challenge is to determine how to use available agents most effectively to obtain consistent, profound, and long-lasting HBV suppression with good safety and convenience in a wide variety of health care settings.
Telbivudine (β-L-2'-deoxythymidine) is an orally bioavailable L-nucleoside with potent and specific anti-HBV activity.11 In preclinical toxicologic testing, telbivudine had no mutagenic or carcinogenic effects and no appreciable embryonic or fetal toxic effects — findings that are particularly relevant for men and women in their reproductive years.12 In initial clinical trials, treatment with telbivudine led to reductions in serum HBV DNA levels that were greater than those observed with lamivudine, and resistance to telbivudine developed less frequently than did resistance to lamivudine.13,14
The present international phase 3 trial, designated Globe, compared the safety and efficacy of treatment with telbivudine with that of lamivudine, the most widely prescribed anti-hepatitis B agent worldwide, in patients with chronic hepatitis B. Patients with hepatitis B e antigen (HBeAg)–positive chronic hepatitis B and those with HBeAg-negative chronic hepatitis B were evaluated to assess differences in therapeutic outcomes that may arise as a result of well-recognized differences in disease characteristics.10,15,16,17 Associations between early suppression of HBV replication and subsequent efficacy and resistance outcomes were assessed.14,18,19
Methods
Patients
Men and women between 16 and 70 years of age who had HBeAg-positive or HBeAg-negative chronic hepatitis B were eligible to participate in the study. The study investigators recruited the patients from March 2003 until April 2004 after a review of medical records and the completion of screening procedures to establish their eligibility for the trial. Chronic hepatitis B was defined by detectable serum hepatitis B surface antigen (HBsAg), a serum alanine aminotransferase level 1.3 to 10.0 times the upper limit of normal, a serum HBV DNA level greater than 6 log10 copies per milliliter, and compatible pretreatment liver histologic findings.
Exclusion criteria included coinfection with hepatitis C, hepatitis D, or the human immunodeficiency virus; evidence of hepatic decompensation, pancreatitis, or hepatocellular carcinoma; previous treatment for hepatitis B with nucleoside or nucleotide analogues or both; treatment with interferon or other immunomodulators within the previous 12 months; other forms of liver disease; a serum creatinine level greater than 1.5 mg per deciliter (133 µmol per liter); a serum amylase or lipase level greater than 1.5 times the upper limit of normal; a prothrombin time prolonged by more than 3 seconds; a serum albumin level less than 3.3 g per deciliter; and a bilirubin level greater than 2.0 mg per deciliter (34 µmol per liter). Eligible patients with a serum alpha fetoprotein level greater than 50 ng per milliliter required exclusion of underlying hepatocellular carcinoma.
Study Design
This randomized, double-blind, active agent–controlled trial was conducted at 112 academic centers in 20 countries. Eligible subjects were randomly assigned centrally in a 1:1 ratio to receive 600 mg of telbivudine or 100 mg of lamivudine once daily as oral tablets. Treatment assignments were stratified according to HBeAg status (positive or negative) and serum alanine aminotransferase level (>2.5 or 
2.5 times the upper limit of normal). Within each stratum, patients were randomly assigned in block sizes of four. Study drugs were supplied in bottles containing telbivudine (Idenix Pharmaceuticals) or overencapsulated lamivudine tablets (GlaxoSmithKline). Primary data analyses were specified for a 52-week treatment period, with the cohort continuing into a second year for longer-term assessments.
Patient histories were obtained, physical examinations were conducted, and venipuncture samples for laboratory assessments were obtained at screening, at baseline, and at weeks 2, 4, 8, 12, 16, 24, 32, 40, 48, and 52. Standardized tests were performed centrally by Quintiles Transnational. Serum HBV DNA levels were quantified by COBAS Amplicor HBV Monitor (Roche Molecular Systems), with a detection limit of 300 copies per milliliter. Serum samples obtained at screening, baseline, and week 2 were prediluted at a 1:1000 ratio to ensure that HBV DNA assessments were within the assay's linear range. Liver-biopsy specimens, collected before treatment and at week 52, were evaluated under blinded conditions by an independent expert with the use of the Knodell and Ishak histologic scoring systems.20,21
The study was conducted in compliance with the ethics principles of the Declaration of Helsinki and was consistent with Good Clinical Practice guidelines and applicable local regulatory requirements, including institutional-review-board approval. All patients provided written informed consent. The informed-consent forms discussed alternative treatment with interferon, lamivudine, and adefovir dipivoxil in countries where these therapies were available. Clinical data were collected and monitored by Quintiles. The sponsors, Idenix Pharmaceuticals and Novartis Pharmaceuticals, conducted predefined statistical analyses; the investigators had full access to the data and contributed substantially to study design, data collection, and data analysis. The manuscript was written in collaboration by the first and last authors; all the other authors were actively involved in review of the manuscript and approval of the final version. The academic authors vouch for the veracity and completeness of the data and data analyses.
Study End Points
The primary efficacy end point was therapeutic response, defined as a reduction in the serum HBV DNA level to fewer than 5 log10 copies per milliliter, as recommended in available treatment guidelines,22,23 coupled with either normalization of the alanine aminotransferase level or loss of detectable HBeAg. This composite end point captures indicators of liver disease and viral suppression used in clinical practice, similar to composite end points used in previous interferon and lamivudine trials.24,25,26,27,28
Histologic response, the key secondary efficacy end point, was defined as a reduction of at least two points in the Knodell necroinflammatory score, with no worsening in the Knodell fibrosis score. Other secondary efficacy measures included changes in the serum HBV DNA level, HBeAg and HBsAg loss and seroconversion, virologic response (a serum HBV DNA level below 5 log10 copies per milliliter and HBeAg loss),29 and normalization of the serum alanine aminotransferase level. Primary treatment failure was defined as completion of at least 24 weeks of treatment without two consecutive measurements of serum HBV DNA levels below 5 log10 copies per milliliter. Safety evaluations included discontinuation of the study drug and analyses of adverse events and graded laboratory abnormalities.
HBV Genotyping, Viral Breakthrough, and Resistance
Viral breakthrough was defined as at least two consecutive determinations of an increase in HBV DNA by at least 1 log10 copy per milliliter from nadir during 48 weeks of therapy, a definition consistent with recent recommendations.30,31 Resistance was defined as viral breakthrough with treatment-emergent resistance mutations.31 HBV DNA was amplified by polymerase chain reaction (PCR) from serum samples at screening or at baseline from all patients, serum samples at week 48 from patients with viral breakthrough, and from patients who received telbivudine and who had more than 3 log10 copies of residual HBV DNA per milliliter at week 52. The 344-codon reverse transcriptase domain of the HBV polymerase gene was sequenced at an independent laboratory (Delft Diagnostic Laboratory). This automated method detects potential resistance mutations that comprise at least 25% of the amplified viral DNA and is consistent with previous methods.32,33,34,35
Early Antiviral Response versus Subsequent Outcomes
Prespecified analyses assessed relationships between early antiviral responses and efficacy and resistance outcomes at 1 year. Patients were categorized at week 24 according to PCR analysis as being negative for serum HBV DNA, as having detectable but fewer than 3 log10 copies of HBV DNA per milliliter, as having from 3 to 4 log10 copies per milliliter, or as having more than 4 log10 copies per milliliter.
Statistical Analysis
The study design provided 99% power to demonstrate noninferiority of telbivudine to lamivudine for therapeutic response, assuming a noninferiority criterion of 15 percentage points, with enrollment of at least 600 HBeAg-positive and 400 HBeAg-negative patients. Analyses were based on all patients randomly assigned to treatment who received at least one dose of study medication. Analyses of histologic response included all patients with pretreatment liver-biopsy specimens that could be evaluated, as in previous studies.32,33,34,35 The primary analysis occurred at week 52, with longer-term assessments at week 104. An independent data and safety monitoring board and an external data-analysis center monitored safety. The patients, investigators, and sponsor remained unaware of treatment assignments throughout the study.
The study was intended to demonstrate effects in both HBeAg subpopulations or in the pooled population, if trends in the subpopulations warranted pooling. The primary end point was assessed by a three-step method.36 First, both HBeAg subpopulations were analyzed separately with an alpha level of 0.04 (95.68% confidence interval). If both subpopulations met the noninferiority criteria (i.e., if confidence intervals for the treatment difference exceeded –15%), treatments would be compared for superiority within each subpopulation. If statistical significance was not established within both HBeAg subpopulations, a statistical test for interaction between the treatment group and HBeAg subpopulations was planned, with significance defined at the alpha level of 0.15.37 With no interaction, a statistical analysis for the overall patient population would be performed with an alpha level of 0.000933 to protect the overall alpha at 0.00125.
Demonstration of noninferiority was a precursor to superiority testing. For the primary efficacy end point, noninferiority criteria were met in both HBeAg subpopulations, but superiority was not established for the primary end point in the HBeAg-negative population. HBeAg subpopulations were not pooled because of this statistical interaction between treatment effect and HBeAg subpopulation. For secondary end points, treatment effects were compared, first for noninferiority and then for superiority, according to a prespecified hierarchy.
Treatment comparisons of categorical end points were assessed by a weighted Cochran–Mantel–Haenszel method adjusted for randomization strata. For continuous variables, analysis of variance was performed with each stratified group as a factor. Reported P values are two-sided and were not adjusted for multiple testing.
Results
Patients
Six hundred eighty-three patients were assigned to receive telbivudine and 687 to receive lamivudine; 3 patients declined to participate further after undergoing randomization. The intention-to-treat population consisted of 921 patients with HBeAg-positive chronic hepatitis B and 446 patients with HBeAg-negative chronic hepatitis B. The treatment groups were well matched at baseline for demographic and disease characteristics (Table 1). Eighteen patients receiving telbivudine (2.6%) and 32 receiving lamivudine (4.7%) withdrew before week 52. Among these, two in the telbivudine group (0.3%) and eight in the lamivudine group (1.2%) discontinued treatment because of adverse events, clinical disease progression, or lack of efficacy. Two of these patients — one with myopathy in the telbivudine group and one with urticaria in the lamivudine group — discontinued treatment because of serious adverse events that possibly were related to the study drugs.
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For all study end points, noninferiority criteria were met for telbivudine as compared with lamivudine, allowing for superiority testing. Among HBeAg-positive patients at week 52, significantly more patients in the telbivudine group than in the lamivudine group had either a therapeutic or a histologic response (Table 2). Among HBeAg-negative patients, the rates of therapeutic and histologic response were similar in both treatment groups at week 52, and thus the noninferiority criteria were met.
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Among both HBeAg-positive patients and HBeAg-negative patients, reduction in serum HBV DNA levels at week 52 was significantly greater in the telbivudine group than in the lamivudine group (Table 2). The difference was evident by week 12 in HBeAg-positive patients (reductions of 5.71 log10 copies per milliliter for telbivudine and 5.42 log10 copies per milliliter for lamivudine, P=0.01) and by week 8 in HBeAg-negative patients (reductions of 4.36 log10 copies per milliliter for telbivudine and 4.08 log10 copies per milliliter for lamivudine, P=0.02), and it persisted through week 52 (Figure 1A and 1B).
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HBeAg and HBsAg Responses
Among HBeAg-positive patients, 25.7% of those in the telbivudine group and 23.3% of those in the lamivudine group had HBeAg loss (P=0.40) and 22.5% of those in the telbivudine group and 21.5% of those in the lamivudine group had HBeAg seroconversion (P=0.73) (Table 2). Among the 69% of patients with pretreatment alanine aminotransferase levels at least twice the upper limit of normal — a group generally considered the best candidates for treatment22,23 — HBeAg loss occurred in 30.8% and 26.2% of patients receiving telbivudine and lamivudine, respectively (P=0.22), and HBeAg seroconversion occurred in 26.6% and 24.1%, respectively (P=0.49). Less than 1% of patients in each treatment group had HBsAg seroconversion.
Biochemical Response
The rates of normalization of serum alanine aminotransferase at week 52 were high (levels more than 70%) in both treatment groups, with results meeting noninferiority criteria in the HBeAg-positive and in the HBeAg-negative subgroups (Table 2).
Additional Histologic Analyses
Among HBeAg-positive patients, the mean Knodell Histologic Activity Index scores (range, 0 to 22, with higher scores indicating more severe disease) improved by 3.92 and 3.64 points in patients receiving telbivudine and in those receiving lamivudine, respectively (difference, 0.28; 95% confidence interval [CI], –0.23 to 0.79); among HBeAg-negative patients, the scores improved by 3.85 and 3.73 points, respectively (difference, 0.12; 95% CI, –0.59 to 0.82). Among HBeAg-positive patients with marked pretreatment bridging fibrosis or cirrhosis and who had Ishak fibrosis scores of 4 to 6 (where 0 indicates no fibrosis and 6 indicates cirrhosis), the Ishak fibrosis scores improved to between 0 and 3 in 68% of patients receiving telbivudine and 61% of patients receiving lamivudine (difference, 7%; 95% CI, –16 to 29%); the corresponding figures for HBeAg-negative patients were 59% and 46% (difference, 13%; 95% CI, –14 to 40%). In contrast, among patients with baseline Ishak fibrosis scores of 0 to 3, progression to a score greater than 3 by week 52 occurred in only 1% of patients in either HBeAg subgroup who were taking either telbivudine or lamivudine.
Breakthrough and Resistance
Viral breakthrough and genotypic resistance were significantly less common in patients receiving telbivudine than in those receiving lamivudine (Table 2). Resistance developed in 5.0% and 2.3% of HBeAg-positive and HBeAg-negative patients who received telbivudine, respectively, as compared with 11.0% and 10.7% of HBeAg-positive and HBeAg-negative patients who received lamivudine, respectively (P<0.001 for both comparisons).
Consistent with previous reports, M204I was the only signature mutation associated with telbivudine resistance; secondary mutations L80I/V and L80I/V+L180M accompanied M204I in 2.2% and 0.3%, respectively, of the patients who received telbivudine.14,38,39 Overall, the M204I mutation was detected in 46 of the 115 patients who received telbivudine and who had serum HBV DNA levels of at least 1000 copies per milliliter at week 52 (including patients with viral breakthrough), representing 6.8% of all telbivudine recipients in the study. Variants harboring mutations at the A181 and L229 codons were detected sporadically, with 16 and 6 occurrences, respectively, among the 115 telbivudine recipients with detectable HBV DNA, but these were not associated with viral breakthrough without concomitant detection of M204I. Lamivudine resistance was based on the signature mutations M204I and M204V; M204V was accompanied by the L180M secondary mutation, whereas M204I was seen alone or with the secondary mutation L80I/V.31,39
Early Viral Suppression and 1-Year Efficacy Outcomes
The distribution of patients according to HBV DNA levels at week 24 (Figure 2) is consistent with the greater viral suppression observed with telbivudine (Figure 1). At week 24, more patients in the telbivudine group than in the lamivudine group were negative for HBV DNA according to PCR, whereas residual HBV DNA levels greater than 4 log10 copies per milliliter were more frequent in patients in the lamivudine group than in those in the telbivudine group.
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Safety and Adverse Events
The frequencies of adverse events through week 52 were similar for patients who received telbivudine and for those who received lamivudine (Table 3). Serious adverse events (defined according to criteria adapted from the Division of AIDS, National Institute of Allergy and Infectious Diseases40), regardless of attributability to study drug, were reported for 18 patients in the telbivudine group (2.6%) and 33 in the lamivudine group (4.8%).
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Grade 3 or 4 elevations in alanine aminotransferase and aspartate aminotransferase levels during treatment were less frequent in the telbivudine group than in the lamivudine group (Table 3). Grade 3 or 4 elevations in alanine aminotransferase levels were noted in 13.1% of patients receiving lamivudine and 12.5% of patients receiving telbivudine who had viral breakthrough. One patient with lamivudine resistance had liver failure and received a liver transplant. After week 24, alanine aminotransferase flares of at least 500 IU per liter and at least twice the baseline value were more common with lamivudine (2.2%) than telbivudine (0.4%).
Discussion
In patients with HBeAg-positive chronic hepatitis B, telbivudine was superior to lamivudine for the primary and key secondary efficacy end points of therapeutic response and histologic response; in HBeAg-negative patients, telbivudine and lamivudine achieved similar rates of therapeutic and histologic response. In both HBeAg-positive and HBeAg-negative patients, telbivudine had greater antiviral efficacy than did lamivudine. The mechanism underlying the effect of pretreatment HBeAg status on therapeutic and histologic response is uncertain, but it may derive from the lower baseline HBV DNA levels and high viral clearance rates observed in HBeAg-negative patients. Results may differ with longer-term follow-up, as treatment-related differences in antiviral potency and resistance assume greater importance for determining therapeutic outcomes.
The lower resistance rates observed with telbivudine than with lamivudine are probably due in part to the greater antiviral efficacy of telbivudine. Consistent with in vitro findings, data concerning clinical resistance confirm the M204I mutation as the primary basis for telbivudine resistance, in contrast to lamivudine resistance, which is associated with either the M204I or the M204V mutation.38 HBV with either of these mutations is less susceptible to inhibition by nucleoside analogues but remains sensitive in vitro to the nucleotide analogues adefovir and tenofovir.31
This study confirms previously described associations between greater reductions in HBV DNA levels at week 24 and better subsequent therapeutic outcomes, including lower resistance.14,18,19 These relationships were similar for both study drugs and may also apply to other agents for hepatitis B. The greater viral suppression achieved with more potent drugs predicts improved clinical outcomes overall.8,10 Future studies of patients with suboptimal responses may determine whether early treatment modification, using drugs with complementary resistance profiles, can improve subsequent outcomes.
The adverse event data in this trial were consistent with previous findings and preclinical toxicologic data12,14,42 and suggest that telbivudine and lamivudine have similar safety profiles. On-treatment aminotransferase flares after the first 6 months of treatment were less frequent with telbivudine, in accord with the lower incidence of viral breakthrough. Elevations in creatine kinase levels were more frequent with telbivudine but were not predictive of muscle-related adverse events. The occurrence of myopathy in a patient treated with telbivudine suggests that any persistent, unexplained muscle-related symptoms should be evaluated promptly.
As for all agents, the clinical role of telbivudine will be determined by efficacy, safety, and resistance considerations. Lamivudine was chosen as the comparator in this trial because it was the treatment of choice when the trial was initiated. Telbivudine has not been compared directly with other recently approved agents, such as entecavir. However, in separate trials, both telbivudine and entecavir have shown greater antiviral effects than have adefovir and lamivudine.33,35,43,44 One year of treatment with pegylated interferon has also been shown to be superior to 1 year of lamivudine when efficacy is assessed 24 weeks after both agents have been stopped.24,25 However, we are unaware of any trials that have compared the efficacy of 1 year of pegylated interferon with that of longer-term treatment with nucleoside or nucleotide analogues.
Maintaining safety and antiviral efficacy is critical with extended therapy. Loss of response due to cumulative resistance, treatment failure, or both has been observed with all nucleoside or nucleotide therapies for hepatitis B. Within 4 years after initiation of treatment, the cumulative incidence of lamivudine resistance approaches 70%.39 Adefovir resistance was observed in 29% of HBeAg-negative patients after 5 years of treatment and in 16 of 38 HBeAg-positive patients with virologic failure after 110 to 279 weeks.45 With entecavir, cumulative resistance was 0.8% at 4 years according to an analysis of 120 of the 663 patients not previously treated with nucleosides from phase 3 trials.46 Similarly, cumulative telbivudine resistance is likely to increase as therapy is extended. Long-term studies are needed to understand the cumulative prevalence and clinical effect of resistance to these agents.
The multiple therapeutic choices now available for hepatitis B will enhance the ability of clinicians to maintain long-term control of HBV replication, ultimately improving clinical outcomes for more patients. These results support telbivudine as an effective therapy for patients with chronic hepatitis B.
Supported by Idenix Pharmaceuticals and Novartis Pharmaceuticals.
Dr. Lai reports receiving consulting fees from Bristol-Myers Squibb, Idenix Pharmaceuticals, and GlaxoSmithKline, lecture fees from Bristol-Myers Squibb, Idenix Pharmaceuticals, and GlaxoSmithKline, and grant support from Bristol-Myers Squibb, Idenix Pharmaceuticals, and Novartis Pharmaceuticals; Dr. Gane, consulting fees from Idenix Pharmaceuticals, Novartis Pharmaceuticals, and GlaxoSmithKline and lecture fees from Novartis Pharmaceuticals and GlaxoSmithKline; Dr. Liaw, consulting fees from Bristol-Myers Squibb, Roche, Schering-Plough, and Novartis, lecture fees from Bristol-Myers Squibb and Novartis, and grant support from Roche, Bristol-Myers Squibb, Novartis, and SciClone Pharmaceuticals; Dr. Heathcote, consulting fees from Idenix Pharmaceuticals and Novartis Pharmaceuticals and grant support from Idenix Pharmaceuticals, Gilead Sciences, Debio, Schering-Plough Pharmaceuticals, Vertex Pharmaceuticals, Human Genome Sciences, Roche, Pharmasett, and Novartis; and Dr. Bzowej, consulting fees from Idenix Pharmaceuticals and Gilead Sciences, lecture fees from Idenix Pharmaceuticals and Novartis Pharmaceuticals, and grant support from Idenix Pharmaceuticals, Gilead Sciences, Roche, Novartis Pharmaceuticals, Vertex Pharmaceuticals, GlaxoSmithKline, and Schering-Plough. Dr. Naoumov reports being an employee of Novartis Pharmaceuticals and receiving consulting fees from Gilead Sciences, Roche, Idenix Pharmaceuticals, and Novartis Pharmaceuticals, lecture fees from GlaxoSmithKline, Schering-Plough, Idenix Pharmaceuticals, and Novartis Pharmaceuticals, and grant support from Idenix Pharmaceuticals and Gilead Sciences. Dr. Di Bisceglie reports receiving consulting fees from Idenix Pharmaceuticals, Roche, Novartis Pharmaceuticals, Vertex Pharmaceuticals, Bristol-Myers Squibb, Pharmasset, Metabasis Therapeutics, SciClone Pharmaceuticals, and Chiron Corporation and grant support from Roche Pharmaceuticals, Gilead Sciences, and Vertex Pharmaceuticals; Dr. Zeuzem, consulting fees from Gilead Sciences, Roche, Idenix Pharmaceuticals, and Novartis Pharmaceuticals and lecture fees from Bristol-Myers Squibb, Gilead Sciences, Roche, Idenix Pharmaceuticals, and Novartis Pharmaceuticals; and Dr. Goodman, consulting fees from Schering-Plough and Gilead Sciences and grant support from Idenix Pharmaceuticals, Bristol-Myers Squibb, SciClone Pharmaceuticals, New England Research Institutes, and GlaxoSmithKline. Dr. Chao reports having been an employee of Idenix Pharmaceuticals until June 2006 and holding equity in Idenix Pharmaceuticals and Bristol-Myers Squibb. Dr. Brown reports being a former employee of Idenix Pharmaceuticals and holding equity in Idenix Pharmaceuticals. Ms. Fielman Constance reports being a full-time employee of Idenix Pharmaceuticals and holding equity in Idenix Pharmaceuticals. No other potential conflict of interest relevant to this article was reported.
We thank Richard Boehme, Ph.D., for assistance with manuscript preparation.
Source Information
From the University Department of Medicine, Queen Mary Hospital, Hong Kong (C.-L.L.); Middlemore Hospital, Auckland, New Zealand (E.G.); Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taipei, Taiwan (Y.-F.L., C.-W.H.); Chiang Mai University, Chiang Mai, Thailand (S.T.); Xi Nan Hospital, Third Military Medical University, Chongqing, China (Y.W.); First Affiliated Hospital, Zhejiang University, Hangzhou, China (Y.C.); University of Toronto, Toronto (E.J.H.); Albert Ludwigs University, Freiburg, Germany (J.R.); Sutter Health, San Francisco (N.B.); University College, London (N.V.N.); Saint Louis University, St. Louis (A.M.D.); Saarland University Hospital, Homburg, Germany (S.Z.); Yonsei University College of Medicine, Seoul, Korea (Y.M.M.); the Armed Forces Institute of Pathology, Washington, DC (Z.G.); and Idenix Pharmaceuticals, Cambridge, MA (G.C., B.F.C., N.A.B.).
Address reprint requests to Dr. Lai at the University Department of Medicine, Queen Mary Hospital, Hong Kong, China, or at hrmelcl{at}hkucc.hku.hk.
References
In addition to the authors, the Globe Study Group included the following investigators: North America — N. Afdhal, M. Bennett, S. Chan, M. Fried, J. Galati, N. Gitlin, E. Godofsky, S.H. Han, T. Hassanein, N. Hilzenrat, M. Khalili, P. Kwan, S. Lee, A. Lok, P. Lynch, A. Min, G. Minuk, M. Mutchnick, T. Nguyen, C. O'Brien, R. Pollard, R. Reindollar, M. Shiffman, M. Tong, N. Tsai, F. Wong; Europe — M. Beaugrand, A. Boron-Kaczmarska, M. Bourliere, M. Buti, Y. Cakaloglu, G. Calleri, J. Crespo Garcia, M. Diago, G. Dusheiko, A. Gladysz, J.D. Grange, S. Gurel, P. Husa, S. Karayalcin, O. Ovunc Kurdas, T. Mach, M. Manns, D. Mutimer, G. Papatheodoridis, A. Perperas, T. Poynard, M. Rizzetto, M. Rodriguez Garcia, D. Samuel, J. Sperl, A. Tran, C. Trepo, P. Urbanek, M. Volfova, J.P. Zarski; Asia — K. Akarawong, T.T. Chang, Y.C. Chao, M. Cho, H. Choi, G. Choudhuri, A. Chutaputti, J.Y. Han, Y. He, J.L. Hou, C.W. Hsu, S.G. Hwang, J.D. Jia, P. Kar, B.S. Kim, D.J. Kim, P. Komolmit, S.T. Lai, C.M. Lee, N.W.Y. Leung, S.G. Lim, W.L. Lu, P. Luengrojanakul, J. Niu, B. Prabhakar, R.R. Rai, S.K. Sarin, E.K. Teo, M. Wan, S.M. Wu, D.Z. Xu, J.Z. Xu, W.L. Yang, Y.K. Yin, X.Q. Zhou, L. Zhu; Australia and New Zealand — P. Angus, D. Crawford, G. Farrell, J. George, C. Moyes, S. Roberts, W. Sievert, S. Strasser, F. Weilert.
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Related Letters:
Telbivudine versus Lamivudine in Patients with Chronic Hepatitis B
Tillmann H. L., McHutchison J. G., Lai C.-L., Gane E., Brown N. A.
Extract |
Full Text |
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N Engl J Med 2008;
358:1517-1518, Apr 3, 2008.
Correspondence
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