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Entecavir for Treatment of Lamivudine-Refractory, HBeAg-Positive Chronic Hepatitis B

2006; Elsevier BV; Volume: 130; Issue: 7 Linguagem: Inglês

10.1053/j.gastro.2006.04.007

1528-0012

Morris Sherman, Cihan Yurdaydìn, Jose D. Sollano, Marcelo José Barbosa Silva, Yun‐Fan Liaw, Janusz Cianciara, Anna Boroń‐Kaczmarska, Paul Martin, Zachary Goodman, Richard J. Colonno, Anne Cross, Gail Denisky, Bruce Kreter, R. Hindes,

Liver Disease Diagnosis and Treatment

Background & Aims: Lamivudine treatment is associated with frequent development of resistant hepatitis B virus (HBV) and loss of treatment benefit. In preclinical and phase II studies, entecavir demonstrated potent antiviral activity against lamivudine-resistant HBV. Methods: In this phase III, double-blind trial, hepatitis B e antigen-positive patients who were refractory to lamivudine therapy (persistent viremia or documented YMDD mutations while receiving lamivudine) were randomized to switch to entecavir 1 mg daily (n = 141) or continue lamivudine 100 mg daily (n = 145) for a minimum of 52 weeks. Two coprimary end points were assessed at 48 weeks: histologic improvement and a composite end point (HBV branched DNA <0.7 MEq/mL and alanine aminotransferase [ALT] <1.25 times the upper limit of normal). Results: Histologic improvement occurred in 55% (68/124) of entecavir-treated vs 28% (32/116) of lamivudine-treated patients (P < .0001). More patients on entecavir than lamivudine achieved the composite end point: 55% (77/141) vs 4% (6/145), respectively (P < .0001). Mean change from baseline in HBV DNA was −5.11 log10 copies/mL for entecavir-treated patients and −0.48 log10 copies/mL for lamivudine-treated patients (P < .0001). Virologic rebound because of entecavir resistance substitutions occurred in 2 of 141 of entecavir-treated patients, and genotypic evidence of resistance was detected in 10 patients. The safety profile of entecavir was comparable to lamivudine with fewer ALT flares on treatment. Conclusions: In patients with lamivudine-refractory chronic hepatitis B, switching to entecavir provides superior histologic improvement, viral load reduction, and ALT normalization compared with continuing lamivudine, with a comparable adverse event profile. Background & Aims: Lamivudine treatment is associated with frequent development of resistant hepatitis B virus (HBV) and loss of treatment benefit. In preclinical and phase II studies, entecavir demonstrated potent antiviral activity against lamivudine-resistant HBV. Methods: In this phase III, double-blind trial, hepatitis B e antigen-positive patients who were refractory to lamivudine therapy (persistent viremia or documented YMDD mutations while receiving lamivudine) were randomized to switch to entecavir 1 mg daily (n = 141) or continue lamivudine 100 mg daily (n = 145) for a minimum of 52 weeks. Two coprimary end points were assessed at 48 weeks: histologic improvement and a composite end point (HBV branched DNA <0.7 MEq/mL and alanine aminotransferase [ALT] <1.25 times the upper limit of normal). Results: Histologic improvement occurred in 55% (68/124) of entecavir-treated vs 28% (32/116) of lamivudine-treated patients (P < .0001). More patients on entecavir than lamivudine achieved the composite end point: 55% (77/141) vs 4% (6/145), respectively (P < .0001). Mean change from baseline in HBV DNA was −5.11 log10 copies/mL for entecavir-treated patients and −0.48 log10 copies/mL for lamivudine-treated patients (P < .0001). Virologic rebound because of entecavir resistance substitutions occurred in 2 of 141 of entecavir-treated patients, and genotypic evidence of resistance was detected in 10 patients. The safety profile of entecavir was comparable to lamivudine with fewer ALT flares on treatment. Conclusions: In patients with lamivudine-refractory chronic hepatitis B, switching to entecavir provides superior histologic improvement, viral load reduction, and ALT normalization compared with continuing lamivudine, with a comparable adverse event profile. See CME Quiz on page 2207. See CME Quiz on page 2207. Chronic hepatitis B virus (HBV) infection has a worldwide prevalence of over 400 million people, which represents more than 5% of the global population.1Lai C.L. Ratziu V. Yuen M.F. Poynard T. Viral hepatitis B.Lancet. 2004; 362: 2089-2093Abstract Full Text Full Text PDF Scopus (679) Google Scholar These patients are at increased risk for development of hepatic cirrhosis, liver failure, and hepatocellular carcinoma (HCC), and over 1 million people die each year from these HBV-associated complications.2Lee W.M. Hepatitis B virus infection.N Engl J Med. 1997; 337: 1733-1745Google Scholar A recently reported cohort study has shown that, among chronic hepatitis B patients, elevated HBV DNA levels are associated with the development of cirrhosis3Iloeje U.H. Yang H.I. Su J. Jen C.L. You S.L. Chen C.J. Predicting liver cirrhosis risk based on the level of circulating hepatitis B viral load.Gastroentrology. 2006; 130: 678-686Abstract Full Text Full Text PDF Scopus (1292) Google Scholar and of HCC.4Chen C.J. Yang H.I. Su J. Jen C.L. You S.L. Lu S.N. Huang G.T. Iloeje U.H. Risk of hepatocellular carcinoma across a biological gradient of serum hepatitis B virus DNA level.JAMA. 2006; 295: 65-73Google Scholar A principal goal of therapy in patients with chronic hepatitis B infection is to arrest and reverse progression of liver damage by suppressing HBV replication.5Liaw Y.F. Leung N. Guan R. Lau G.K.K. Merican I. McCaughan G. Gane E. Kao J.H. Omata M. Asian-Pacific consensus update working party on chronic hepatitis BAsian-Pacific consensus statement on the management of chronic hepatitis B a 2005 update.Liver Int. 2005; 25: 472-489Google Scholar Lamivudine was the first nucleoside analogue to be introduced as therapy for chronic hepatitis B infection and remained the only available nucleoside antiviral for several years. A major limitation of lamivudine therapy is the emergence of drug-resistant HBV from substitutions at M204I/V (within the tyrosine-methionine-aspartate-aspartate YMDD motif of the viral DNA polymerase) that are frequently accompanied by an L180M substitution. Genotypic evidence of lamivudine resistance precedes virologic rebounds by several months. Although lamivudine-resistant strains of HBV emerged in up to 24% of patients after 1 year and as many as 70% of patients after 4 years of treatment, the clinical implications of lamivudine resistance were not immediately evident.6Locarnini S. Hepatitis B viral resistance mechanisms and diagnosis.J Hepatol. 2003; 39: S124-S132Google Scholar, 7Lai C.L. Dienstag J. Schiff E. Leung N.W.Y. Atkins M. Hunt C. Brown N. Woessner M. Boehme R. Condreay L. Prevalence and clinical correlates of YMDD variants during lamivudine therapy for patients with chronic hepatitis B.Clin Infect Dis. 2003; 36: 687-696Google Scholar Early studies found that patients with lamivudine-resistant HBV who continued to receive lamivudine maintained lower serum HBV DNA and alanine aminotransferase (ALT) levels than baseline and continued to experience hepatitis B e antigen (HBeAg) seroconversion (albeit at a lower rate than patients with wild-type HBV).8Leung N.W.Y. Lai C.L. Chang T.T. Guan R. Lee C.M. Ng K.Y. Lim S.G. Wu P.C. Dent J.C. Edmundson S. Condreay L.D. Chien R.N. Extended lamivudine treatment in patients with chronic hepatitis B enhances hepatitis B e antigen seroconversion rates results after 3 years of therapy.Hepatology. 2001; 33: 1527-1532Google Scholar, 9Liaw Y.F. Leung N.W.Y. Chang T.T. Guan R. Tai D.I. Ng K.Y. Chien R.N. Dent J. Roman L. Edmundson S. Lai C.L. Effects of extended lamivudine therapy in Asian patients with chronic hepatitis B.Gastroenterology. 2000; 119: 172-180Abstract Full Text Full Text PDF Scopus (709) Google Scholar, 10Leung N.W.Y. Clinical experience with lamivudine.Semin Liver Dis. 2002; 22: 15-21Google Scholar In addition, discontinuation of lamivudine in patients with lamivudine-resistant HBV was associated with hepatic flares.11Chen C.H. Lee C.M. Lu S.N. Wang J.H. Tung H.D. Hung C.H. Chen W.J. Changchien C.S. Comparison of clinical outcome between patients continuing and discontinuing lamivudine therapy after biochemical breakthrough of YMDD mutants.J Hepatol. 2004; 41: 454-461Abstract Full Text Full Text PDF Scopus (39) Google Scholar Thus, continuing lamivudine therapy was recommended and generally accepted, despite emergence of resistance substitutions.12Lok A.S.F. McMahon B.J. Chronic hepatitis B.Hepatology. 2001; 34: 1225-1241Google Scholar, 13Lok A.S.F. Heathcote E.J. Hoofnagle J.H. Management of hepatitis B 2000—summary of a workshop.Gastroenterology. 2001; 120: 1828-1853Google Scholar It has subsequently been shown that, although lamivudine-resistant mutants are replication impaired, additional compensatory mutations are selected during continued lamivudine exposure that can restore replication fitness.14Ono-Nita S.K. Kato N. Shiratori Y. YMDD motif in hepatitis B virus DNA polymerase influences on replication and lamivudine resistance a study by in-vitro full-length viral DNA transfection.Hepatology. 1999; 29: 939-945Google Scholar, 15Yeh C.T. Chien R.N. Chu C.M. Liaw Y.F. Clearance of the original hepatitis B virus YMDD-motif mutants with emergence of distinct lamivudine-resistant mutants during prolonged lamivudine therapy.Hepatology. 2000; 31: 1318-1326Google Scholar, 16Bock C.T. Tillman H.L. Torresi J. Klempnauer J. Locarnini S. Manns M.P. Trautwein C. Selection of hepatitis B virus polymerase mutants with enhanced replication by lamivudine treatment after liver transplantation.Gastroenterology. 2002; 122: 264-273Abstract Full Text Full Text PDF Scopus (187) Google Scholar Accumulated evidence now points to the negative consequences of continuing lamivudine after the development of resistance. Increases in viral replication and serum ALT levels,17Lai C.L. Chien R.N. Leung N.W.Y. Chang T.T. Guan R. Tai D.I. Ng K.Y. Wu P.C. Dent J.C. Barber J. Stephenson S.L. Gray D.F. A one-year trial of lamivudine for chronic hepatitis B.N Engl J Med. 1998; 339: 61-68Google Scholar, 18Lau D.T.Y. Khokhar M.F. Doo E. Ghany M. Herion D. Park Y. Kleiner D.E. Schmid P. Condreay L.D. Gauthier J. Kuhns M.C. Liang T.J. Hoofnagle J.H. Long-term therapy of chronic hepatitis B with lamivudine.Hepatology. 2000; 32: 828-834Google Scholar, 19Liaw Y.F. Chien R.N. Yeh C.T. Tsai S.L. Chu C.M. Acute exacerbation and hepatitis B virus clearance after emergence of YMDD motif mutation during lamivudine therapy.Hepatology. 1999; 30: 567-572Google Scholar, 20Papatheodoridis G.V. Dimou E. Laras A. Papadimitropoulos V. Hadziyannis S.J. Course of virologic breakthroughs under long-term lamivudine in HBeAg-negative precore mutant HBV liver disease.Hepatology. 2002; 36: 219-226Google Scholar, 21Chang T.T. Lai C.L. Chien R.N. Guan R. Lim S.G. Lee C.M. Ng K.Y. Nicholls G.J. Dent J.C. Leung N.W.Y. Four years of lamivudine treatment in Chinese patients with chronic hepatitis B.J Gastroenterol Hepatol. 2004; 19: 1276-1282Google Scholar flares of hepatic disease,11Chen C.H. Lee C.M. Lu S.N. Wang J.H. Tung H.D. Hung C.H. Chen W.J. Changchien C.S. Comparison of clinical outcome between patients continuing and discontinuing lamivudine therapy after biochemical breakthrough of YMDD mutants.J Hepatol. 2004; 41: 454-461Abstract Full Text Full Text PDF Scopus (39) Google Scholar, 19Liaw Y.F. Chien R.N. Yeh C.T. Tsai S.L. Chu C.M. Acute exacerbation and hepatitis B virus clearance after emergence of YMDD motif mutation during lamivudine therapy.Hepatology. 1999; 30: 567-572Google Scholar, 22Lok A.S.F. Lai C.L. Leung N. Yao G.B. Cui Z.Y. Schiff E.R. Dienstag J.L. Heathcote E.J. Little N.R. Griffiths D.A. Gardner S.D. Castiglia M. Long-term safety of lamivudine treatment in patients with chronic hepatitis B.Gastroenterology. 2003; 125: 1714-1722Google Scholar reversal of previous histologic improvement,8Leung N.W.Y. Lai C.L. Chang T.T. Guan R. Lee C.M. Ng K.Y. Lim S.G. Wu P.C. Dent J.C. Edmundson S. Condreay L.D. Chien R.N. Extended lamivudine treatment in patients with chronic hepatitis B enhances hepatitis B e antigen seroconversion rates results after 3 years of therapy.Hepatology. 2001; 33: 1527-1532Google Scholar, 23Dienstag J.L. Goldin R.D. Heathcote E.J. Hann H.W.L. Woessner M. Stephenson S.L. Gardner S. Gray D.F. Schiff E.R. Histological outcome during long-term lamivudine therapy.Gastroenterology. 2003; 124: 105-117Google Scholar and decreased rates of HBeAg seroconversion9Liaw Y.F. Leung N.W.Y. Chang T.T. Guan R. Tai D.I. Ng K.Y. Chien R.N. Dent J. Roman L. Edmundson S. Lai C.L. Effects of extended lamivudine therapy in Asian patients with chronic hepatitis B.Gastroenterology. 2000; 119: 172-180Abstract Full Text Full Text PDF Scopus (709) Google Scholar, 10Leung N.W.Y. Clinical experience with lamivudine.Semin Liver Dis. 2002; 22: 15-21Google Scholar may occur. Liaw et al recently found no benefit to continuing lamivudine therapy compared with stopping treatment in patients with lamivudine-resistant HBV.24Liaw Y.F. Chien R.N. Yeh C.T. No benefit to continue lamivudine therapy after emergence of YMDD mutations.Antivir Ther. 2004; 9: 257-262Google Scholar Among chronic hepatitis B patients with compensated cirrhosis, lamivudine resistance has been associated with hepatic decompensation and the development of HCC.25Di Marco V. Di Stefano R. Ferraro D. Almasio P.L. Bonura C. Giglio M. Parisi P. Cappello M. Alaimo G. Craxi A. HBV-DNA suppression and disease course in HBV cirrhosis patients on long-term lamivudine therapy.Antivir Ther. 2005; 10: 431-439Google Scholar, 26Andreone P. Gramenzi A. Cursaro C. Biselli M. Camma C. Trevisani F. Bernardi M. High risk of hepatocellular carcinoma in anti-HBe positive liver cirrhosis patients developing lamivudine resistance.J Viral Hepat. 2004; 11: 439-442Google Scholar When this study began, the only nucleoside treatment option for patients who had developed lamivudine resistance was continuation of lamivudine. Treatment guidelines at the time recommended continuing lamivudine to avoid reappearance of wild-type virus and to maintain viral load and ALT below baseline levels.12Lok A.S.F. McMahon B.J. Chronic hepatitis B.Hepatology. 2001; 34: 1225-1241Google Scholar, 13Lok A.S.F. Heathcote E.J. Hoofnagle J.H. Management of hepatitis B 2000—summary of a workshop.Gastroenterology. 2001; 120: 1828-1853Google Scholar A double-blind, phase II dose-ranging study of entecavir in HBeAg-positive and -negative lamivudine-refractory patients found that a 1 mg dose of entecavir for 48 weeks provided a reduction in HBV DNA of greater than 5 log10 copies/mL, with a safety profile comparable with that of lamivudine.27Chang T.T. Hadziyannis S. Cianciara J. Rizzetto M. Schiff E.R. Pastore G. Bacon B. Poynard T. Rutkiewicz V. Thomas N. Denisky G. Joshi S. A dose-ranging study of the efficacy and tolerability of entecavir in lamivudine-refractory chronic hepatitis B patients.Gastroenterology. 2005; 129: 1198-1209Abstract Full Text Full Text PDF Scopus (230) Google Scholar Therefore, in this phase III trial in lamivudine-refractory patients, switching patients to entecavir 1 mg daily was compared with continuing lamivudine 100 mg daily for impact on liver histology, suppression of viral load, serologic response, and normalization of ALT. Eligible patients included hepatitis B surface antigen (HBsAg)-positive men and women 16 years or older who were receiving ongoing lamivudine therapy and were refractory to that therapy. This was defined as any of the following: persistently detectable HBV DNA by branched DNA (bDNA) assay after at least 36 weeks of lamivudine; recurrence of detectable HBV DNA by bDNA assay on 2 determinations after achieving undetectable HBV DNA (by bDNA assay) on lamivudine; recurrence and persistence of HBV replication after discontinuing lamivudine provided that lamivudine had been reintroduced and maintained for at least 12 weeks prior to screening; or documented YMDD mutation and HBV viremia on lamivudine regardless of duration of therapy. Patients were HBeAg positive and had ALT levels 1.3–10 times the upper limit of normal (ULN) and HBV DNA levels ≥3.0 MEq/mL by Quantiplex bDNA assay (Chiron Diagnostics Corp, Walpole, MA) at screening. Patients had compensated liver function with total serum bilirubin ≤2.5 mg/dL (≤42.75 μmol/L); prothrombin time ≤3 seconds longer than the normal control or international normalized ratio (INR) ≤1.5; serum albumin ≥3.0 g/dL; and no history of variceal bleeding, ascites requiring diuretics or paracentesis, or encephalopathy. Patients were required to have evidence of chronic hepatitis upon liver biopsy that was performed at screening or within 1 year prior to randomization and following clinical evidence of incomplete response to lamivudine. Exclusion criteria included the following: coinfection with hepatitis C, hepatitis D, or human immunodeficiency virus; other forms of liver disease; prior therapy with a nucleos(t)ide analogue with activity against HBV other than lamivudine for ≥12 weeks duration or given within 6 months prior to randomization; use of interferon α or thymosin-α1 within 6 months prior to randomization; α-fetoprotein (AFP) >100 ng/mL; and prior treatment with entecavir. This was a randomized, double-blind, double-dummy, active controlled trial. Patients were recruited from 84 sites in North America (28), South America (5), Europe and the Middle East (28), Australia (6), and Asia (17) and randomized to entecavir 1 mg daily or continued lamivudine 100 mg daily for a minimum of 52 weeks. There was no interruption in lamivudine therapy before randomization. Written informed consent was obtained from all patients, and each study site obtained ethics committee/institutional review board approval. The study was conducted in accordance with the ethical principles of the Declaration of Helsinki and was consistent with Good Clinical Practice and applicable local regulatory requirements. Patients were screened within 4 weeks of randomization to determine study eligibility. Eligible patients were randomized centrally using an interactive voice response system (IVRS; Quintiles Transnational). Randomization was accomplished using blocks of permuted treatment assignments and was stratified by study site. Randomized patients were evaluated at weeks 2 and 4 and every 4 weeks thereafter for 52 weeks. At each visit, patients were evaluated for compliance with study medication and adverse events. Hematology, biochemistry, urinalysis, and prothrombin time/INR were assessed. At baseline and weeks 12, 24, 36, and 48 during dosing, HBV serologies and HBV DNA level by Quantiplex bDNA assay were assessed. HBV DNA levels using Roche COBAS Amplicor PCR assay (version 2.0, limit of quantification: 300 copies/mL; Roche Molecular Systems, Alameda, CA) were assessed at baseline and weeks 24, 36, and 48. Investigators, patients, and study sponsor were blinded to results and treatment assignment until week 52 when the week 48 results of HBV by bDNA assay and HBeAg status were made available for the purpose of clinical management decisions. A liver biopsy specimen was obtained during screening, unless a biopsy was performed within 52 weeks of randomization and following clinical evidence of incomplete response to lamivudine. A second biopsy specimen was obtained at week 48. Paired baseline and week 48 biopsy specimens were assessed by a central histopathologist (Z.G.), who was blinded to treatment assignment and sample sequence. Patients with missing or inadequate biopsy samples at week 48 were considered treatment failures. Clinical management decisions were made at week 52, based on week 48 results. Response to treatment was defined as HBV DNA <0.7 MEq/mL by bDNA assay and loss of HBeAg at week 48; patients achieving this protocol-defined response were to discontinue therapy and be followed for 24 weeks off treatment. Virologic-only response was defined as HBV DNA <0.7 MEq/mL but positive for HBeAg at week 48; patients achieving a virologic-only response were to continue blinded study medication until week 96 or until a response was achieved, whichever occurred first. Nonresponse was defined as HBV DNA ≥0.7 MEq/mL by bDNA assay at week 48; patients with nonresponse were to discontinue blinded therapy and begin marketed anti-HBV therapy as recommended by their physician or enroll in an entecavir rollover protocol. The 2 coprimary efficacy end points were histologic improvement, defined as a ≥2-point decrease in the Knodell necroinflammatory score and no worsening of the Knodell fibrosis score on the week 48 liver biopsy specimen compared with baseline28Knodell R.G. Ishak K.G. Black W.C. Chen T.S. Craig R. Kaplowitz N. Kiernan T.W. Wollman J. Formulation and application of a numerical scoring system for assessing histological activity in asymptomatic chronic active hepatitis.Hepatology. 1981; 1: 431-435Google Scholar; and achievement of the composite end point, defined as serum HBV DNA <0.7 MEq/mL by bDNA assay and ALT <1.25 × ULN at week 48. For analysis of the histologic improvement end point, evaluable patients had adequate baseline biopsy specimens with a Knodell necroinflammatory score of at least 2. Secondary efficacy end points included the mean log10 change from baseline in serum HBV DNA and the proportions of patients with HBV DNA <300 copies/mL by PCR assay; a decrease of ≥1 point in the Ishak fibrosis score; rates of HBeAg loss and seroconversion (loss of HBeAg and appearance of anti-HBe); and proportions of patients achieving ALT normalization, defined per protocol as ALT <1.25 × ULN and subsequently reanalyzed using the more stringent definition of ALT ≤1 × ULN. The more stringent analysis of ALT ≤1 × ULN is presented here, except when ALT levels are used to determine the composite coprimary end point. Patients who achieved a protocol-defined response at week 48 and discontinued therapy were followed off treatment. Among responders, sustained response was defined as persistence of HBV DNA 2 × baseline and 10 × ULN) and off treatment (defined as ALT elevations of >2 × reference and 10 × ULN, in which the reference level was defined as the lesser of the baseline and the end-of-dosing ALT value) were also tabulated. All HBV DNA samples from treated patients were analyzed at baseline for substitutions associated with lamivudine resistance (M204V/I and L180M) using the Inno-LiPA HBV DR assay (Innogenetics NV, Ghent, Belgium). All available paired baseline and 48-week samples from entecavir subjects underwent genotypic analysis for emerging resistance substitutions. HBV DNA was extracted, PCR was amplified, and amino acids 1–344 of the reverse transcriptase were sequenced as described elsewhere.29Tenney D.J. Levine S.M. Rose R.E. Walsh A.W. Weinheimer S.P. Discotto L. Plym M. Pokornowski K. Yu C.F. Angus P. Ayres A. Bartholomeusz A. Sievert W. Thompson G. Warner N. Locarnini S. Colonno R.J. Clinical emergence of entecavir-resistant hepatitis B virus requires additional substitutions in virus already resistant to lamivudine.Antimicrob Agents Chemother. 2004; 48: 3498-3507Google Scholar Virologic rebound was defined as a confirmed ≥1 log10 increase from nadir in HBV DNA by PCR assay. The cohort included all randomized patients who received at least 1 dose of study medication (modified intention-to-treat method), and patients with missing measurements at week 48 were counted as failures (noncompleter = failure). The 2 coprimary end points, histologic improvement and the composite end point, were evaluated separately for each subject. A Bonferroni adjustment was applied for testing superiority with an overall 2-sided significance level of 5%. For histologic improvement, the planned sample size of 135 patients per group provided 90% power to detect superiority of entecavir to lamivudine, assuming a response rate of 25% for lamivudine and ≥50% for entecavir; a 25% rate of missing data; and a 2-sided significance level of 2.5%. For the composite end point, the planned sample size of 135 patients per group provided 90% power to detect superiority of entecavir to lamivudine, assuming a response rate of 15% for lamivudine and ≥35% for entecavir; a 5% rate of missing data; and a 2-sided significance level of 2.5%. Entecavir was superior to lamivudine for each respective coprimary end point if the 97.5% confidence interval for the estimate of the treatment differences was greater than zero. Comparisons of the means of continuous parameters used t tests based on linear regression models, adjusted for baseline measurements. Mean differences were based on patients with both baseline and week 48 measurements. Binary variables were summarized by counts and proportions. Confidence intervals for differences in proportions were based on the normal approximation to the binomial distribution. Of 420 patients enrolled and screened, 293 were randomized (Figure 1). Patients were not randomized for the following reasons: 108 did not meet inclusion criteria; 18 withdrew consent; and 1 completed screening after randomization closed. Two hundred eighty-six patients received at least 1 dose of blinded study drug (entecavir 141, lamivudine 145 patients). The 2 treatment groups were well-balanced for demographics and disease characteristics at baseline (Table 1). Overall, 54% of treated patients had received interferon prior to study entry. Five (4%) patients in the entecavir group and 3 (2%) patients in the lamivudine group were positive for HBeAg during screening and negative for HBeAg at baseline. Of the 11 entecavir-treated and 4 lamivudine-treated patients with seroconversion at week 48, 2 entecavir-treated and 1 lamivudine-treated patient seroconverted in the period between screening and randomization; these patients continued in the study. Of the 286 treated subjects, 281 (98%) had a baseline liver biopsy, and 240 patients (84%) had evaluable baseline liver biopsies.Table 1Demographics and HBV Baseline CharacteristicsEntecavir 1 mg (n = 141)Lamivudine 100 mg (n = 145)Age, median, yr (range)38 (16–74)40 (17–70)Male, n (%)105 (74)112 (77)Race, n (%) White83 (59)93 (64) Asian57 (40)50 (34) Other1 (<1)2 (1)Region, n (%) Europe62 (44)72 (50) Asia35 (25)36 (25) North America31 (22)24 (17) South America13 (9)13 (9)Viral genotype, n (%) A37 (26)32 (22) B23 (16)17 (12) C27 (19)28 (19) D45 (32)56 (39) F4 (3)3 (2)Other/indeterminate/missing5 (4)9 (6)HBV DNA by PCR, log10 copies/mL, mean ± SD9.48 ± 1.819.24 ± 1.56HBeAg positive, n (%)aFive (4%) patients in the entecavir group and 3 (2%) patients in the lamivudine group were positive for HBeAg during screening and negative for HBeAg at baseline.136 (96)142 (98)Detectable LVDr mutations, n (%)118 (84)124 (86)Serum ALT (U/L) mean ± SD123.9 ± 109.72131.9 ± 165.11Knodell necroinflammatory score, mean ± SDbTreated patients with adequate baseline biopsies: n = 135 for entecavir, n = 133 for lamivudine.6.5 ± 3.236.5 ± 3.41Knodell fibrosis score, mean ± SDbTreated patients with adequate baseline biopsies: n = 135 for entecavir, n = 133 for lamivudine.1.7 ± 1.191.8 ± 1.18Bridging fibrosis (%)2331Cirrhosis (%)106Prior interferon, n (%)74 (52)80 (55)a Five (4%) patients in the entecavir group and 3 (2%) patients in the lamivudine group were positive for HBeAg during screening and negative for HBeAg at baseline.b Treated patients with adequate baseline biopsies: n = 135 for entecavir, n = 133 for lamivudine. Open table in a new tab Most randomized patients (88%) completed the first year of dosing. During the first year, fewer patients in the entecavir group (<1%) than in the lamivudine group (5%) discontinued treatment because of adverse events. Five lamivudine-treated patients (3%) and 2 entecavir-treated patients (1%) withdrew consent during the first year. A greater proportion of patients in the entecavir group than in the lamivudine group continued to the second year of treatment (62% vs 19%, respectively), primarily because of achieving a virologic-only response at week 48. Compliance with week 48 biopsies was high; 251 (88%) had a week 48 biopsy. The observed rate of missing biopsies was slightly higher in the lamivudine group (16%) vs the entecavir group (12%). This difference was largely due to the greater number of discontinuations because of adverse events in the lamivudine group. Entecavir was superior to lamivudine for the proportion of patients demonstrating histologic improvement at week 48, with 55% and 28%, respectively, achieving this coprimary end point (P < .0001) (Table 2). Entecavir was also superior to lamivudine for the proportion of patients demonstrating improvement in the Ishak fibrosis score (34% vs 16%, respectively, P = .0019). Fewer patients in the entecavir group (11%) than in the lamivudine group (26%) experienced worsening of fibrosis, defined as a ≥1-point increase in the Ishak fibrosis score compared with baseline.Table 2Histologic and Ishak Fibrosis Improvement at Week 48End pointEntecavir 1 mg (n = 141)Lamivudine 100 mg (n = 145)Evaluable baseline biopsy specimens, naEvaluable patients had adequate baseline biopsy specimens and Knodell necroinflammatory score ≥2.124116Histologic improvement, n (%)bImprovement of ≥2 points in the necroinflammatory component of the Knodell score with no worsening in the fibrosis component of the score.68 (55)32 (28) Difference interval (entecavir-lamivudine)27.3 P value (97.5% confidence estimate)<.0001 (13.6–40.9)No histologic improvement, n (%)42 (34)66 (57)Knodell necroinflammatory score, meancTreated subjects with evaluable histology pairs: there were 110 entecavir patients and 98 lamivudine patients. Missing week 48 biopsy specimens were reported for 11% and 10% of entecavir and 16% and 15% of lamivudine patients for necroinflammation and fibrosis grading, respectively. Bas