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• W2014279976 abstract "Background & Aims: Entecavir is a nucleoside analogue with potent in vitro activity against lamivudine-resistant hepatitis B virus (HBV). This randomized, dose-ranging, phase 2 study compared the efficacy and safety of entecavir with lamivudine in lamivudine-refractory patients. Methods: Hepatitis B e antigen (HBeAg)-positive and -negative patients (n = 182), viremic despite lamivudine treatment for ≥24 weeks or having documented lamivudine resistance substitutions, were switched directly to entecavir (1.0, 0.5, or 0.1 mg daily) or continued on lamivudine (100 mg daily) for up to 76 weeks. Results: At week 24, significantly more patients receiving entecavir 1.0 mg (79%) or 0.5 mg (51%) had undetectable HBV DNA levels by branched chain DNA assay compared with lamivudine (13%; P < .0001). Entecavir 1.0 mg was superior to entecavir 0.5 mg for this end point (P < .01). After 48 weeks, mean reductions in HBV DNA levels were 5.06, 4.46, and 2.85 log10 copies/mL on entecavir 1.0, 0.5, and 0.1 mg, respectively, significantly higher than 1.37 log10 copies/mL on lamivudine. Significantly higher proportions of patients achieved normalization of alanine aminotransferase levels on entecavir 1.0, 0.5, and 0.1 mg (68%, 59%, and 47%, respectively) than on lamivudine (6%). One virologic rebound due to resistance occurred (in the 0.5-mg group). Conclusions: In HBeAg-positive and HBeAg-negative lamivudine-refractory patients, treatment with entecavir 1.0 and 0.5 mg daily was well tolerated and resulted in significant reductions in HBV DNA levels and normalization of alanine aminotransferase levels. One milligram of entecavir was more effective than 0.5 mg in this population. Background & Aims: Entecavir is a nucleoside analogue with potent in vitro activity against lamivudine-resistant hepatitis B virus (HBV). This randomized, dose-ranging, phase 2 study compared the efficacy and safety of entecavir with lamivudine in lamivudine-refractory patients. Methods: Hepatitis B e antigen (HBeAg)-positive and -negative patients (n = 182), viremic despite lamivudine treatment for ≥24 weeks or having documented lamivudine resistance substitutions, were switched directly to entecavir (1.0, 0.5, or 0.1 mg daily) or continued on lamivudine (100 mg daily) for up to 76 weeks. Results: At week 24, significantly more patients receiving entecavir 1.0 mg (79%) or 0.5 mg (51%) had undetectable HBV DNA levels by branched chain DNA assay compared with lamivudine (13%; P < .0001). Entecavir 1.0 mg was superior to entecavir 0.5 mg for this end point (P < .01). After 48 weeks, mean reductions in HBV DNA levels were 5.06, 4.46, and 2.85 log10 copies/mL on entecavir 1.0, 0.5, and 0.1 mg, respectively, significantly higher than 1.37 log10 copies/mL on lamivudine. Significantly higher proportions of patients achieved normalization of alanine aminotransferase levels on entecavir 1.0, 0.5, and 0.1 mg (68%, 59%, and 47%, respectively) than on lamivudine (6%). One virologic rebound due to resistance occurred (in the 0.5-mg group). Conclusions: In HBeAg-positive and HBeAg-negative lamivudine-refractory patients, treatment with entecavir 1.0 and 0.5 mg daily was well tolerated and resulted in significant reductions in HBV DNA levels and normalization of alanine aminotransferase levels. One milligram of entecavir was more effective than 0.5 mg in this population. Chronic hepatitis B infection affects more than 350 million people worldwide.1Lee W.M. Hepatitis B virus infection.N Engl J Med. 1997; 337: 1733-1745Google Scholar, 2World Health OrganizationFact sheet WHO/204. Hepatitis B. World Health Organization, Geneva, Switzerland2003Google Scholar These patients are at increased risk of morbidity and mortality without treatment, and 15%–25% die from chronic liver disease.3Hepatitis B fact sheet. National Center for Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, GA2004Google Scholar Before the introduction of nucleoside analogues, interferon alfa was the most widely used chemotherapeutic treatment for hepatitis B virus (HBV) infection. Treatment with interferon alfa results in hepatitis B e antigen (HBeAg) seroconversion in about one third of patients chronically infected with HBV but is often poorly tolerated.4Krogsgaard K. Bindslev N. Christensen E. Craxi A. Schlichting P. Schalm S. Carreno V. Trepo C. Gerken G. Thomas H.C. The treatment effect of alpha interferon in chronic hepatitis B is independent of pre-treatment variables. Results based on individual patient data from 10 clinical controlled trials. European Concerted Action on Viral Hepatitis.J Hepatol. 1994; 21 (Eurohep): 646-655Scopus (0) Google Scholar Lamivudine was the first nucleoside analogue to be approved for the treatment of chronic HBV infection.5Dienstag J.L. Schiff E.R. Wright T.L. Perrillo R.P. Hann H.W. Goodman Z. Crowther L. Condreay L.D. Woessner M. Rubin M. Brown N.A. Lamivudine as initial treatment for chronic hepatitis B in the United States.N Engl J Med. 1999; 341: 1256-1263Google Scholar, 6Nevens F. Main J. Honkoop P. Tyrrell D.L. Barber J. Sullivan M.T. Fevery J. De Man R.A. Thomas H.C. Lamivudine therapy for chronic hepatitis B a six-month randomized dose-ranging study.Gastroenterology. 1997; 113: 1258-1263Abstract Full Text Full Text PDF Scopus (294) Google Scholar, 7Schalm S.W. Heathcote J. Cianciara J. Farrell G. Sherman M. Willems B. Dhillon A. Moorat A. Barber J. Gray D.F. Lamivudine and alpha interferon combination treatment of patients with chronic hepatitis B infection a randomised trial.Gut. 2000; 46: 562-568Google Scholar The short-term efficacy of lamivudine therapy has been well documented; however, clinical effectiveness has been limited by the frequent development of lamivudine-resistant mutants.8Liaw Y.F. Impact of YMDD mutations during lamivudine therapy in patients with chronic hepatitis B.Antivir Chem Chemother. 2001; 12: 67-71Google Scholar, 9Ono S.K. Kato N. Shiratori Y. Kato J. Goto T. Schinazi R.F. Carrilho F.J. Omata M. The polymerase L528M mutation cooperates with nucleotide binding-site mutations, increasing hepatitis B virus replication and drug resistance.J Clin Invest. 2001; 107: 449-455Google Scholar, 10Zoulim F. Detection of hepatitis B virus resistance to antivirals.J Clin Virol. 2001; 21: 243-253Google Scholar, 11Lau D.T. Khokhar M.F. Doo E. Ghany M.G. 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 Lamivudine resistance is principally associated with amino acid substitutions in the conserved tyrosine-methionine-aspartate-aspartate (YMDD) motif of the HBV RNA–dependent DNA polymerase,8Liaw Y.F. Impact of YMDD mutations during lamivudine therapy in patients with chronic hepatitis B.Antivir Chem Chemother. 2001; 12: 67-71Google Scholar, 12Stuyver L.J. Locarnini S.A. Lok A. Richman D.D. Carman W.F. Dienstag J.L. Schinazi R.F. Nomenclature for antiviral-resistant human hepatitis B virus mutations in the polymerase region.Hepatology. 2001; 33: 751-757Google Scholar, 13Allen M.I. Deslauriers M. Andrews C.W. Tipples G.A. Walters K.A. Tyrrell D.L. Brown N. Condreay L.D. Lamivudine Clinical Investigation GroupIdentification and characterization of mutations in hepatitis B virus resistant to lamivudine.Hepatology. 1998; 27: 1670-1677Google Scholar although genotypic changes outside this region have also been reported to contribute to lamivudine resistance.9Ono S.K. Kato N. Shiratori Y. Kato J. Goto T. Schinazi R.F. Carrilho F.J. Omata M. The polymerase L528M mutation cooperates with nucleotide binding-site mutations, increasing hepatitis B virus replication and drug resistance.J Clin Invest. 2001; 107: 449-455Google Scholar, 14Niesters H.G. Honkoop P. Haagsma E.B. De Man R.A. Schalm S.W. Osterhaus A.D. Identification of more than one mutation in the hepatitis B virus polymerase gene arising during prolonged lamivudine treatment.J Infect Dis. 1998; 177: 1382-1385Google Scholar The emergence of lamivudine resistance–associated substitutions is usually accompanied by a rebound in viral load and elevation of alanine aminotransferase (ALT) levels.15Papatheodoridis G.V. Dimou E. Papadimitropoulos V. Nucleoside analogues for chronic hepatitis B antiviral efficacy and viral resistance.Am J Gastroenterol. 2002; 97: 1618-1628Google Scholar Although these increases generally remain below pretreatment levels, marked flares of ALT levels or acute exacerbation of hepatitis may occur and can lead to hepatic decompensation or even death.8Liaw Y.F. Impact of YMDD mutations during lamivudine therapy in patients with chronic hepatitis B.Antivir Chem Chemother. 2001; 12: 67-71Google Scholar, 10Zoulim F. Detection of hepatitis B virus resistance to antivirals.J Clin Virol. 2001; 21: 243-253Google Scholar, 16Mutimer D. Hepatitis B virus infection resistance to antiviral agents.J Clin Virol. 2001; 21: 239-242Google Scholar, 17Paik Y.H. Chung H.Y. Ryu W.S. Lee K.S. Lee J.S. Kim J.H. Lee C.K. Chon C.Y. Moon Y.M. Han K.H. Emergence of YMDD motif mutant of hepatitis B virus during short-term lamivudine therapy in South Korea.J Hepatol. 2001; 35: 92-98Google Scholar, 18Liaw 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, 19Ayres A. Bartholomeusz A. Lau G. Lam K.C. Lee J.Y. Locarnini S. Lamivudine and Famciclovir resistant hepatitis B virus associated with fatal hepatic failure.J Clin Virol. 2003; 27: 111-116Google Scholar, 20Bonacini M. Kurz A. Locarnini S. Ayres A. Gibbs C. Fulminant hepatitis B due to a lamivudine-resistant mutant of HBV in a patient coinfected with HIV.Gastroenterology. 2002; 122: 244-245Abstract Full Text Full Text PDF Scopus (42) Google Scholar, 21Kim J.W. Lee H.S. Woo G.H. Yoon J.H. Jang J.J. Chi J.G. Kim C.Y. Fatal submassive hepatic necrosis associated with tyrosine-methionine-aspartate-aspartate-motif mutation of hepatitis B virus after long-term lamivudine therapy.Clin Infect Dis. 2001; 33: 403-405Google Scholar Lamivudine therapy is often continued in lamivudine-refractory patients because viral loads may remain lower than pretreatment levels and discontinuation of the therapy may be associated with a significant increase in viral replication and flare of ALT levels.11Lau D.T. Khokhar M.F. Doo E. Ghany M.G. 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, 18Liaw 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, 22Honkoop P. De Man R.A. Niesters H.G. Zondervan P.E. Schalm S.W. Acute exacerbation of chronic hepatitis B virus infection after withdrawal of lamivudine therapy.Hepatology. 2000; 32: 635-639Google Scholar, 23Fontaine H. Driss F. Lagneau J.L. Hepatitis B virus reactivation after lamivudine discontinuation.Hepatology. 1999; 30 (abstr): 349AGoogle Scholar, 24Song B.C. Suh D.J. Lee H.C. Chung Y.H. Lee Y.S. Hepatitis B e antigen seroconversion after lamivudine therapy is not durable in patients with chronic hepatitis B in Korea.Hepatology. 2000; 32: 803-806Google Scholar, 25Lok A.S. 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 More recent literature, however, has raised questions about the benefit of continuing lamivudine therapy in these patients.26Liaw 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 Entecavir is a potent and highly selective inhibitor of HBV with no effect on mitochondrial DNA synthesis.27Innaimo S.F. Seifer M. Bisacchi G.S. Standring D.N. Zahler R. Colonno R.J. Identification of BMS-200475 as a potent and selective inhibitor of hepatitis B virus.Antimicrob Agents Chemother. 1997; 41: 1444-1448Crossref Google Scholar, 28Tanji N. Tanji K. Kambham N. Markowitz G.S. Bell A. D’Agati V.D. Adefovir nephrotoxicity possible role of mitochondrial DNA depletion.Hum Pathol. 2001; 32: 734-740Google Scholar In vitro studies have shown that, with a median effective concentration of 0.4 nmol/L, entecavir has more than 300 times greater potency than lamivudine in suppressing wild-type HBV. In the presence of lamivudine resistance–associated substitutions at residues rtL180M and rtM204I, the median effective concentration of entecavir is increased to approximately 0.026 μmol/L.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 The combination of intrinsic potency and efficient conversion to the active triphosphate result in predicted intracellular concentrations above those needed to inhibit lamivudine-resistant strains of HBV containing both single and double lamivudine resistance–associated substitutions.9Ono S.K. Kato N. Shiratori Y. Kato J. Goto T. Schinazi R.F. Carrilho F.J. Omata M. The polymerase L528M mutation cooperates with nucleotide binding-site mutations, increasing hepatitis B virus replication and drug resistance.J Clin Invest. 2001; 107: 449-455Google Scholar, 30Levine S. Hernandez D. Yamanaka G. Zhang S. Rose R. Weinheimer S. Colonno R.J. Efficacies of entecavir against lamivudine-resistant hepatitis B virus replication and recombinant polymerases in vitro.Antimicrob Agents Chemother. 2002; 46: 2525-2532Google Scholar However, in lamivudine-resistant viruses, additional substitutions at residues rtT184, rtS202, or rtM250 further reduced entecavir susceptibility.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 The activity of entecavir was initially established in animal models of viral hepatitis.31Colonno R.J. Genovesi E.V. Medina I. Lamb L. Durham S.K. Huang M.L. Corey L. Littlejohn M. Locarnini S. Tennant B.C. Rose B. Clark J.M. Long-term entecavir treatment results in sustained antiviral efficacy and prolonged life span in the woodchuck model of chronic hepatitis infection.J Infect Dis. 2001; 184: 1236-1245Google Scholar, 32Genovesi E.V. Lamb L. Medina I. Taylor D. Seifer M. Innaimo S. Colonno R.J. Standring D.N. Clark J.M. Efficacy of the carbocyclic 2′-deoxyguanosine nucleoside BMS-200475 in the woodchuck model of hepatitis B virus infection.Antimicrob Agents Chemother. 1998; 42: 3209-3217Google Scholar, 33Marion P.L. Salazar F.H. Winters M.A. Colonno R.J. Potent efficacy of entecavir (BMS-200475) in a duck model of hepatitis B virus replication.Antimicrob Agents Chemother. 2002; 46: 82-88Google Scholar Subsequently, in nucleoside-naive patients with chronic hepatitis B infection, two phase 2 studies showed that entecavir at doses ranging from 0.01 to 1.0 mg/day was effective in reducing HBV DNA levels up to 4.7 log10 from baseline after 22 weeks.34De Man R.A. Wolters L.M. Nevens F. Chua D. Sherman M. Lai C.L. Gadano A. Lee Y. Mazzotta F. Thomas N. Dehertogh D. Safety and efficacy of oral entecavir given for 28 days in patients with chronic hepatitis B virus infection.Hepatology. 2001; 34: 578-582Google Scholar, 35Lai C.L. Rosmawati M. Lao J. Van Vlierberghe H. Anderson F.H. Thomas N. Dehertogh D. Entecavir is superior to lamivudine in reducing hepatitis B virus DNA in patients with chronic hepatitis B infection.Gastroenterology. 2002; 123: 1831-1838Abstract Full Text Full Text PDF Scopus (279) Google Scholar In the second of these studies, doses of 0.5 mg/day and 0.1 mg/day of entecavir were both superior to 100 mg/day of lamivudine in reducing HBV levels.35Lai C.L. Rosmawati M. Lao J. Van Vlierberghe H. Anderson F.H. Thomas N. Dehertogh D. Entecavir is superior to lamivudine in reducing hepatitis B virus DNA in patients with chronic hepatitis B infection.Gastroenterology. 2002; 123: 1831-1838Abstract Full Text Full Text PDF Scopus (279) Google Scholar The current trial was a double-blind, randomized, dose-ranging, phase 2 study designed to assess the efficacy and safety of entecavir versus continued lamivudine in patients with chronic hepatitis B infection who remained viremic after at least 24 weeks of lamivudine therapy or had documented lamivudine resistance–associated substitutions. Three different doses of entecavir (1.0, 0.5, and 0.1 mg daily) were evaluated with the aim of selecting an optimal dose for further study in phase 3 clinical trials in lamivudine-refractory patients. We conducted a randomized (1:1:1:1), double-blind, multicenter, multinational study comparing 3 doses of entecavir monotherapy (1.0, 0.5, and 0.1 mg daily) with continued lamivudine (100 mg daily) for up to 76 weeks in adults with chronic HBV infection who remained viremic despite treatment with lamivudine (Figure 1). Both HBeAg-positive and -negative patients were included. Randomization was performed using a centralized interactive voice randomization system and was stratified by site. Lamivudine treatment was discontinued and study medication initiated within 72 hours of randomization. Study medication was discontinued at week 28 in patients who had a <1 log10 reduction in HBV DNA levels by branched chain DNA (bDNA) assay at week 24. Patients with a ≥1 log10 reduction in HBV DNA levels continued on assigned therapy and a second assessment of virologic response was made at week 52, based on the virologic, serologic, and biochemical results from week 48. A protocol-defined complete response was HBV DNA level <0.7 MEq/mL by Quantiplex bDNA assay (Bayer Diagnostics, Emeryville, CA), serum ALT level <1.25 times the upper limit of normal (ULN) (World Health Organization toxicity grade 0), and loss of HBeAg (for patients who were HBeAg positive at baseline). A partial response was defined as HBV DNA level <0.7 MEq/mL by bDNA assay with persistence of HBeAg (in those patients who were HBeAg positive at baseline) or serum ALT level ≥1.25 times the ULN. Patients with a complete response had their medication discontinued and were actively monitored for an additional 24 weeks to assess whether the response was sustained off treatment. Patients with a partial response continued on blinded therapy for up to 76 weeks until they achieved a complete response or until the open-label phase of the study (entecavir 1.0 mg) became available at the study site. Patients with an insufficient virologic response at weeks 24 or 48 or who had a relapse during postdosing follow-up could either enter an open-label rollover study of combination therapy with entecavir 1.0 mg plus lamivudine 100 mg once daily (protocol AI463-901) or be treated according to their physician’s discretion. A relapse was defined as HBV DNA level ≥0.7 MEq/mL by bDNA assay, reappearance of HBeAg, or ALT level ≥1.25 times the ULN on 2 determinations at least 2 weeks apart during 24 weeks of follow-up. The study was powered to show differences in reduction of HBV DNA levels between entecavir and lamivudine after 24 weeks to allow for the possibility of a high number of treatment discontinuations at week 28 in the lamivudine group. The primary efficacy end point was the proportion of patients in each treatment group who achieved undetectable HBV DNA levels as measured by bDNA assay (<0.7 MEq/mL) at week 24. Secondary efficacy end points included the proportion of patients who achieved undetectable HBV DNA levels by bDNA assay at week 48, the mean reduction in log10 HBV DNA by polymerase chain reaction (PCR) assay at weeks 24 and 48, and the proportion of patients with undetectable HBV DNA levels by PCR assay (<400 copies/mL) at weeks 24 and 48. Loss of HBeAg and antibody to hepatitis B e antigen seroconversion in patients who were positive for HBeAg at baseline and normalization of serum ALT levels (<1.25 times the ULN) in patients with elevated ALT levels at baseline were also assessed. Eligible patients were male and female patients older than 16 years with chronic HBV infection who were considered to be lamivudine refractory on the basis of documented viremia after receiving at least 24 weeks of lamivudine therapy or documented evidence of a lamivudine resistance–associated substitution while receiving lamivudine. Viremia was defined as HBV DNA levels ≥10 pg/mL by the Abbott column-based hybridization assay (Abbott, Abbott Park, IL), ≥25 pg/mL by the Digene chemiluminescent molecular hybridization assay (Digene, Silver Spring, MD), or ≥10 MEq/mL by the Chiron bDNA assay (Chiron, Emeryville, CA), on 2 determinations at least 2 weeks apart. Patients were required to have aspartate aminotransferase and ALT levels ≤10 times the ULN and well-compensated liver function documented by a prothrombin time that was no more than 3 seconds longer than normal (or international normalized ratio ≤2.23), serum albumin level ≥3.0 g/dL, and total serum bilirubin level ≤2.5 mg/dL (≤42.75 μmol/L). Patients were excluded if they were coinfected with hepatitis C virus, hepatitis delta virus, or human immunodeficiency virus; had another form of liver disease or a liver transplant; had received immunomodulator therapy (interferon alfa or thymosin α1) within 24 weeks before randomization; or had received prior antiviral therapy with nucleoside or nucleotide analogues other than lamivudine for more than 4 weeks. For women of childbearing potential, pregnancy was also an exclusion criterion. Written informed consent was obtained from all patients. The study was conducted in accordance with the ethical principles of the Declaration of Helsinki and in accordance with good clinical practice and local regulatory requirements. Clinical evaluations and serum chemistry levels were obtained at baseline, at weeks 2 and 4, and every 4 weeks thereafter. HBV DNA levels were measured by Quantiplex bDNA assay (lower limit of detection, 0.7 MEq/mL or 2.5 pg/mL) on day 1 and at weeks 2, 4, 12, 24, 36, 48, 60, and 76. HBV DNA levels were also measured by PCR on day 1 and at weeks 24, 48, and 76 (Roche Amplicor HBV Monitor; Roche, Indianapolis, IN; lower limit of detection, 200 copies/mL). The analysis of proportions of patients with undetectable HBV DNA levels by PCR used a lower limit of 400 copies/mL to be consistent with previous studies.36Hadziyannis S.J. Tassopoulos N.C. Heathcote E.J. Chang T.T. Kitis G. Rizzetto M. Marcellin P. Lim S.G. Goodman Z. Wulfsohn M.S. Xiong S. Fry J. Brosgart C.L. Adefovir dipivoxil for the treatment of hepatitis B e antigen-negative chronic hepatitis B.N Engl J Med. 2003; 348: 800-807Google Scholar HBV serologies (hepatitis B surface antigen, antibody to hepatitis B surface antigen, HBeAg, and antibody to hepatitis B e antigen) were obtained at day 1 and at weeks 12, 24, 48, and 76. Safety assessments included clinical and laboratory evaluations, patient interviews and physical examinations to monitor for adverse events, discontinuations due to adverse events, and other serious adverse events including deaths. Serious adverse events were reported without regard to duration of dosing. To provide clinically relevant safety analyses, safety data were collected during 3 analysis periods: on blinded treatment, postblinded dosing off-treatment follow-up, and 24-week postblinded dosing follow-up. The on-blinded treatment analyses included data for all treated patients, with observations made from baseline to the end of blinded dosing plus 5 days or to the start of open-label therapy. Safety analyses for the postblinded dosing off-treatment follow-up period included treated patients with postblinded dosing follow-up data obtained while patients were receiving no alternative hepatitis B therapy. Measurements were obtained from the end of blinded dosing plus 6 days to the start of alternative hepatitis B therapy or to the end of postblinded dosing follow-up, whichever came first. The 24-week postblinded dosing follow-up analysis was performed similarly to the postblinded dosing off-treatment follow-up analysis but included events regardless of the administration of alternative HBV therapy. HBV DNA was extracted from patient serum samples, and the HBV reverse transciptase (RT) domain of the HBV polymerase gene was PCR amplified and the PCR product sequenced directly. The nucleotide sequence of the HBV RT domain corresponding to amino acid residues 52–34412Stuyver L.J. Locarnini S.A. Lok A. Richman D.D. Carman W.F. Dienstag J.L. Schinazi R.F. Nomenclature for antiviral-resistant human hepatitis B virus mutations in the polymerase region.Hepatology. 2001; 33: 751-757Google Scholar was determined for all available day-1, week-24, and week-48 patient samples. Emergent substitutions in the RT were identified by comparison of baseline and on-treatment sequences. Identification of conserved and polymorphic residue positions was accomplished by comparison with an alignment of 250 published wild-type HBV RT sequences (GenBank). In addition, lamivudine resistance–associated signature substitutions were reported, including substitutions rtL180M and rtM204I or rtM204V. The planned sample size of 45 patients per group had 90% power to demonstrate superiority of a dose of entecavir compared with lamivudine for the primary end point (HBV DNA <0.7 MEq/mL by bDNA assay at week 24) with a 2-sided significance level of .05 adjusted for multiple comparisons, assuming a 20% success rate for lamivudine and a 60% success rate for the entecavir dose. This sample size would also provide 90% power to demonstrate a 1.0 log10 difference between doses of entecavir in mean HBV DNA levels measured at week 24 using the PCR assay (assuming a within-group SD of 1.25 log10 in these measurements and a 2-sided significance level of .05). Data on efficacy and safety were analyzed for all randomized patients who received 1 or more doses of study medication. For the primary efficacy analysis, the difference between treatment groups in proportions of patients with undetectable HBV DNA levels, the 98.3% confidence intervals, and the P values were computed using a normal approximation to the binomial distribution. A dose of entecavir was determined to be superior to lamivudine if the P value was <.0167 (an overall .05 2-sided significance level adjusted for 3 comparisons). Other binary end points were assessed similarly with 95% confidence intervals; entecavir was determined to be superior to lamivudine if the P value was <.05. Patients who discontinued treatment or had missing data were regarded as having failed to respond to therapy. Comparisons of the means of continuous parameters were performed using t tests based on linear regression adjustment for baseline HBV DNA levels. Mean differences were based on patients who completed dosing. Missing measurements were ignored. Values reported as less than the limit of quantitation were assigned a value of 1 copy less than the limit (eg, 0.699999 MEq/mL for bDNA assay and 199 copies/mL for the PCR assay). Patients were enrolled at 41 study centers in 14 countries (Australia, Canada, France, Greece, Italy, Malaysia, The Netherlands, Pakistan, the Philippines, Poland, Singapore, Spain, Taiwan, and the United States) from April to October 2000. Of the 182 randomized patients, 181 received at least 1 dose of blinded study drug (45 patients in the lamivudine arm and 42, 47, and 47 patients in the entecavir 1.0 mg, 0.5 mg, and 0.1 mg arms, respectively). Demographic and baseline characteristics were similar across the 4 treatment groups (Table 1). The majority of patients were HBeAg positive (67%), white (61%), male (81%), and had elevated ALT levels (66%) at study entry. Forty-five percent of patients had previously failed to respond to interferon alfa therapy. Of the 181 patients, 157 (87%) had lamivudine resistance–associated substitutions at baseline.Table 1Demographic and Baseline Characteristics of the PatientsCharacteristicEntecavir 1.0 mg (n = 42)Entecavir 0.5 mg (n = 47)Entecavir 0.1 mg (n = 47)Lamivudine 100 mg (n = 45)Male, no. (%)39 (93)37 (79)36 (77)34 (76)Age (y), mean ± SD48 ± 1344 ± 1346 ± 1248 ± 15Weight (kg), mean ± SD77 ± 1577 ± 2573 ± 1477 ± 20Ethnicity, no. (%) White26 (62)28 (60)28 (60)29 (64) Asian/Pacific Islander12 (29)15 (32)17 (36)14 (31) Black3 (7)1 (2)00 Hispanic/Latino02 (4)01 (2) Other1 (2)1 (2)2 (4)1 (2)HBV DNA, mean ± SD log10 copies/mL by Roche PCR assay9.07 ± 1.549.29 ± 0.828.99 ± 1.199.28 ± 0.82 log10 MEq/mL by Chiron bDNA assay2.48 ± 0.982.42 ± 0.842.25 ± 0.822.41 ± 0.87HBeAg positive, no. (%)27 (64)32 (68)30 (64)32 (71)ALT (U/L), mean ± SD141 ± 186113 ± 11685 ± 67110 ± 97 >1.25 times the ULN, no. (%)28 (67)29 (62)30 (64)33 (73)Prior interferon treatment, no. (%)20 (48)20 (43)19 (40)23 (51)Lamivudine resistance-associated substitution, no. (%)38 (90)40 (85)40 (85)39 (87)HBV genotype, no. (%) D14 (33)15 (32)19 (40)14 (31) A13 (31)17 (36)9 (19)18 (40) C8 (19)7 (15)13 (28)8 (18) B5 (12)7 (15)4 (9)5 (11) Other2 (4)1 (2)2 (4)0 (0) Open table in a new tab A total of 172 patients (" @default.
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