FREE NEJM E-TOC    HOME   |   SUBSCRIBE   |   CURRENT ISSUE   |   PAST ISSUES   |   COLLECTIONS   |   Search Term  Advanced Search

Sign in | Get NEJM's E-Mail Table of Contents — Free | Subscribe

Previous Volume 348:808-816 February 27, 2003 Number 9 Next

	Full Text PDF PDA Full Text PowerPoint Slide Set Editorial by Mailliard, M. E. Letters Add to Personal Archive Add to Citation Manager Notify a Friend E-mail When Cited E-mail When Letters Appear Related Article PubMed Citation

ABSTRACT

Background In preclinical and phase 2 studies, adefovir dipivoxil demonstrated potent activity against hepatitis B virus (HBV), including lamivudine-resistant strains.

Methods We randomly assigned 515 patients with chronic hepatitis B who were positive for hepatitis B e antigen (HBeAg) to receive 10 mg of adefovir dipivoxil (172 patients), 30 mg of adefovir dipivoxil (173), or placebo (170) daily for 48 weeks. The primary end point was histologic improvement in the 10-mg group as compared with the placebo group.

Results After 48 weeks of treatment, significantly more patients who received 10 mg or 30 mg of adefovir dipivoxil per day than who received placebo had histologic improvement (53 percent [P<0.001], 59 percent [P<0.001], and 25 percent, respectively), a reduction in serum HBV DNA levels (by a median of 3.52 [P<0.001], 4.76 [P<0.001], and 0.55 log copies per milliliter, respectively), undetectable levels (fewer than 400 copies per milliliter) of serum HBV DNA (21 percent [P<0.001], 39 percent [P<0.001], and 0 percent, respectively), normalization of alanine aminotransferase levels (48 percent [P<0.001], 55 percent [P<0.001], and 16 percent, respectively), and HBeAg seroconversion (12 percent [P=0.049], 14 percent [P=0.01], and 6 percent, respectively). No adefovir-associated resistance mutations were identified in the HBV DNA polymerase gene. The safety profile of the 10-mg dose of adefovir dipivoxil was similar to that of placebo; however, there was a higher frequency of adverse events and renal laboratory abnormalities in the group given 30 mg of adefovir dipivoxil per day.

Conclusions In patients with HBeAg-positive chronic hepatitis B, 48 weeks of 10 mg or 30 mg of adefovir dipivoxil per day resulted in histologic liver improvement, reduced serum HBV DNA and alanine aminotransferase levels, and increased the rates of HBeAg seroconversion. The 10-mg dose has a favorable risk–benefit profile for long-term treatment. No adefovir-associated resistance mutations were identified in the HBV DNA polymerase gene.

Source Information

From the Service d'Hépatologie, INSERM Unité 481, and Centre de Recherches Claude Bernard sur les Hépatites Virales, Hôpital Beaujon, Clichy, France (P.M.); the Department of Internal Medicine, National Cheng Kung University Hospital, Tainan, Taiwan (T.-T.C.); the Division of Gastroenterology, National University Hospital, Singapore (S.G.L.); the Liver Center, Huntington Medical Research Institutes, Pasadena, Calif. (M.J.T.); the Department of Medicine, Monash University and Monash Medical Centre, Melbourne, Australia (W.S.); the Division of Gastroenterology, Virginia Commonwealth University Health System, Richmond (M.L.S.); the Center for Liver Diseases, University of Miami School of Medicine, and the Miami Veterans Affairs Medical Center, Miami (L.J.); the Armed Forces Institute of Pathology, Washington, D.C. (Z.G.); and Gilead Sciences, Foster City, Calif. (M.S.W., S.X., J.F., C.L.B.).

Address reprint requests to Dr. Marcellin at the Service d'Hépatologie, INSERM Unité 481, and Centre de Recherches Claude Bernard sur les Hépatites Virales, Hôpital Beaujon, 100 Blvd. du Général Leclerc, 92110 Clichy, France, or at marcellin{at}bichat.inserm.fr.

Full Text of this Article

Related Letters:

Adefovir Dipivoxil for Hepatitis B e Antigen–Positive Chronic Hepatitis B
Mukherjee S., Marcellin P., the Adefovir Dipivoxil 437 Study Group
Extract | Full Text | PDF  
N Engl J Med 2003; 348:2468, Jun 12, 2003. Correspondence

This article has been cited by other articles:

• Michalak, T. I., Zhang, H., Churchill, N. D., Larsson, T., Johansson, N.-G., Oberg, B. (2009). Profound Antiviral Effect of Oral Administration of MIV-210 on Chronic Hepadnaviral Infection in a Woodchuck Model of Hepatitis B. Antimicrob. Agents Chemother. 53: 3803-3814 [Abstract] [Full Text]  
• Scarsi, K. K., Darin, K. M. (2009). Chronic Hepatitis B Infection: Principles of Therapy. Journal of Pharmacy Practice 22: 359-387 [Abstract]  
• Shamliyan, T. A., MacDonald, R., Shaukat, A., Taylor, B. C., Yuan, J.-M., Johnson, J. R., Tacklind, J., Rutks, I., Kane, R. L., Wilt, T. J. (2009). Antiviral Therapy for Adults With Chronic Hepatitis B: A Systematic Review for a National Institutes of Health Consensus Development Conference. ANN INTERN MED 150: 111-124 [Abstract] [Full Text]  
• Marcellin, P., Heathcote, E. J., Buti, M., Gane, E., de Man, R. A., Krastev, Z., Germanidis, G., Lee, S. S., Flisiak, R., Kaita, K., Manns, M., Kotzev, I., Tchernev, K., Buggisch, P., Weilert, F., Kurdas, O. O., Shiffman, M. L., Trinh, H., Washington, M. K., Sorbel, J., Anderson, J., Snow-Lampart, A., Mondou, E., Quinn, J., Rousseau, F. (2008). Tenofovir Disoproxil Fumarate versus Adefovir Dipivoxil for Chronic Hepatitis B. NEJM 359: 2442-2455 [Abstract] [Full Text]  
• Dienstag, J. L. (2008). Hepatitis B Virus Infection. NEJM 359: 1486-1500 [Full Text]  
• Menne, S., Butler, S. D., George, A. L., Tochkov, I. A., Zhu, Y., Xiong, S., Gerin, J. L., Cote, P. J., Tennant, B. C. (2008). Antiviral Effects of Lamivudine, Emtricitabine, Adefovir Dipivoxil, and Tenofovir Disoproxil Fumarate Administered Orally Alone and in Combination to Woodchucks with Chronic Woodchuck Hepatitis Virus Infection. Antimicrob. Agents Chemother. 52: 3617-3632 [Abstract] [Full Text]  
• Lucifora, J., Durantel, D., Belloni, L., Barraud, L., Villet, S., Vincent, I. E., Margeridon-Thermet, S., Hantz, O., Kay, A., Levrero, M., Zoulim, F. (2008). Initiation of hepatitis B virus genome replication and production of infectious virus following delivery in HepG2 cells by novel recombinant baculovirus vector. J. Gen. Virol. 89: 1819-1828 [Abstract] [Full Text]  
• Sokal, E. M., Kelly, D., Wirth, S., Mizerski, J., Dhawan, A., Frederick, D. (2008). The Pharmacokinetics and Safety of Adefovir Dipivoxil in Children and Adolescents With Chronic Hepatitis B Virus Infection. J Clin Pharmacol 48: 512-517 [Abstract] [Full Text]  
• Cooksley, H., Chokshi, S., Maayan, Y., Wedemeyer, H., Andreone, P., Gilson, R., Warnes, T., Paganin, S., Zoulim, F., Frederick, D., Neumann, A. U., Brosgart, C. L., Naoumov, N. V. (2008). Hepatitis B Virus e Antigen Loss during Adefovir Dipivoxil Therapy Is Associated with Enhanced Virus-Specific CD4+ T-Cell Reactivity. Antimicrob. Agents Chemother. 52: 312-320 [Abstract] [Full Text]  
• Lai, C.-L., Gane, E., Liaw, Y.-F., Hsu, C.-W., Thongsawat, S., Wang, Y., Chen, Y., Heathcote, E. J., Rasenack, J., Bzowej, N., Naoumov, N. V., Di Bisceglie, A. M., Zeuzem, S., Moon, Y. M., Goodman, Z., Chao, G., Constance, B. F., Brown, N. A., the Globe Study Group, (2007). Telbivudine versus Lamivudine in Patients with Chronic Hepatitis B. NEJM 357: 2576-2588 [Abstract] [Full Text]  
• Feld, J. J., Ghany, M. G. (2007). Evolution of Therapy for Chronic Hepatitis B: Progressing from the Simple to the Complex. ANN INTERN MED 147: 806-808 [Full Text]  
• Chan, H. L.Y., Heathcote, E. J., Marcellin, P., Lai, C.-L., Cho, M., Moon, Y. M., Chao, Y.-C., Myers, R. P., Minuk, G. Y., Jeffers, L., Sievert, W., Bzowej, N., Harb, G., Kaiser, R., Qiao, X.-J., Brown, N. A., and the 018 Study Group, (2007). Treatment of Hepatitis B e Antigen Positive Chronic Hepatitis with Telbivudine or Adefovir: A Randomized Trial. ANN INTERN MED 147: 745-754 [Abstract] [Full Text]  
• Guo, H., Jiang, D., Zhou, T., Cuconati, A., Block, T. M., Guo, J.-T. (2007). Characterization of the Intracellular Deproteinized Relaxed Circular DNA of Hepatitis B Virus: an Intermediate of Covalently Closed Circular DNA Formation. J. Virol. 81: 12472-12484 [Abstract] [Full Text]  
• Moriconi, F., Colombatto, P., Coco, B., Ciccorossi, P., Oliveri, F., Flichman, D., Maina, A. M., Sacco, R., Bonino, F., Brunetto, M. R. (2007). Emergence of hepatitis B virus quasispecies with lower susceptibility to nucleos(t)ide analogues during lamivudine treatment. J Antimicrob Chemother 60: 341-349 [Abstract] [Full Text]  
• Valsamakis, A. (2007). Molecular Testing in the Diagnosis and Management of Chronic Hepatitis B. Clin. Microbiol. Rev. 20: 426-439 [Abstract] [Full Text]  
• Lim, C. Y., Kowdley, K. V. (2007). Optimal duration of therapy in HBV-related cirrhosis. J Antimicrob Chemother 60: 2-6 [Abstract] [Full Text]  
• Brunelle, M. N., Lucifora, J., Neyts, J., Villet, S., Holy, A., Trepo, C., Zoulim, F. (2007). In Vitro Activity of 2,4-Diamino-6-[2-(Phosphonomethoxy)Ethoxy]-Pyrimidine against Multidrug-Resistant Hepatitis B Virus Mutants. Antimicrob. Agents Chemother. 51: 2240-2243 [Abstract] [Full Text]  
• Delaney, W. E. IV (2007). Progress in the treatment of chronic hepatitis B: long-term experience with adefovir dipivoxil. J Antimicrob Chemother 59: 827-832 [Abstract] [Full Text]  
• Tenney, D. J., Rose, R. E., Baldick, C. J., Levine, S. M., Pokornowski, K. A., Walsh, A. W., Fang, J., Yu, C.-F., Zhang, S., Mazzucco, C. E., Eggers, B., Hsu, M., Plym, M. J., Poundstone, P., Yang, J., Colonno, R. J. (2007). Two-Year Assessment of Entecavir Resistance in Lamivudine-Refractory Hepatitis B Virus Patients Reveals Different Clinical Outcomes Depending on the Resistance Substitutions Present. Antimicrob. Agents Chemother. 51: 902-911 [Abstract] [Full Text]  
• Thio, C. L., Astemborski, J., Bashirova, A., Mosbruger, T., Greer, S., Witt, M. D., Goedert, J. J., Hilgartner, M., Majeske, A., O'Brien, S. J., Thomas, D. L., Carrington, M. (2007). Genetic Protection against Hepatitis B Virus Conferred by CCR5{Delta}32: Evidence that CCR5 Contributes to Viral Persistence. J. Virol. 81: 441-445 [Abstract] [Full Text]  
• Saikia, N., Talukdar, R., Mazumder, S., Khanna, S., Tandon, R. (2007). Management of patients with HBeAg-negative chronic hepatitis B. Postgrad. Med. J. 83: 32-39 [Abstract] [Full Text]  
• Yeon, J E, Yoo, W, Hong, S P, Chang, Y J, Yu, S K, Kim, J H, Seo, Y S, Chung, H J, Moon, M S, Kim, S-O, Byun, K S, Lee, C H (2006). Resistance to adefovir dipivoxil in lamivudine resistant chronic hepatitis B patients treated with adefovir dipivoxil. Gut 55: 1488-1495 [Abstract] [Full Text]  
• Grattagliano, I., Palmieri, V. O, Portincasa, P., Palasciano, G. (2006). Adefovir Dipivoxyl for the Treatment of Delta-Related Liver Cirrhosis. The Annals of Pharmacotherapy 40: 1681-1684 [Abstract] [Full Text]  
• Calabrese, L H, Zein, N N, Vassilopoulos, D (2006). Hepatitis B virus (HBV) reactivation with immunosuppressive therapy in rheumatic diseases: assessment and preventive strategies. Ann Rheum Dis 65: 983-989 [Abstract] [Full Text]  
• Chang, T.-T., Lai, C.-L., Schildgen, O., Sirma, H., Gerlich, W. (2006). Hepatitis B virus with primary resistance to adefovir.. NEJM 355: 322-323 [Full Text]  
• Kelly, D. (2006). Viral hepatitis B and C in children. JRSM 99: 353-357 [Full Text]  
• Osborn, M. K., Lok, A. S. F. (2006). Antiviral options for the treatment of chronic hepatitis B. J Antimicrob Chemother 57: 1030-1034 [Abstract] [Full Text]  
• Lim, S. G., Krastev, Z., Ng, T. M., Mechkov, G., Kotzev, I. A., Chan, S., Mondou, E., Snow, A., Sorbel, J., Rousseau, F., for the FTCB-204 Study Group, (2006). Randomized, Double-Blind Study of Emtricitabine (FTC) plus Clevudine versus FTC Alone in Treatment of Chronic Hepatitis B.. Antimicrob. Agents Chemother. 50: 1642-1648 [Abstract] [Full Text]  
• Honeck, P., Weigel, M., Kwon, S.T., Alken, P., Bross, S. (2006). Assisted procreation in cases of hepatitis B, hepatitis C or human immunodeficiency virus infection of the male partner. Hum Reprod 21: 1117-1121 [Abstract] [Full Text]  
• Schildgen, O., Sirma, H., Funk, A., Olotu, C., Wend, U. C., Hartmann, H., Helm, M., Rockstroh, J. K., Willems, W. R., Will, H., Gerlich, W. H. (2006). Variant of hepatitis B virus with primary resistance to adefovir.. NEJM 354: 1807-1812 [Abstract] [Full Text]  
• Chang, T.-T., Gish, R. G., de Man, R., Gadano, A., Sollano, J., Chao, Y.-C., Lok, A. S., Han, K.-H., Goodman, Z., Zhu, J., Cross, A., DeHertogh, D., Wilber, R., Colonno, R., Apelian, D., the BEHoLD AI463022 Study Group, (2006). A Comparison of Entecavir and Lamivudine for HBeAg-Positive Chronic Hepatitis B. NEJM 354: 1001-1010 [Abstract] [Full Text]  
• Hoofnagle, J. H. (2006). Hepatitis B -- Preventable and Now Treatable. NEJM 354: 1074-1076 [Full Text]  
• Jacquard, A.-C., Brunelle, M.-N., Pichoud, C., Durantel, D., Carrouee-Durantel, S., Trepo, C., Zoulim, F. (2006). In Vitro Characterization of the Anti-Hepatitis B Virus Activity and Cross-Resistance Profile of 2',3'-Dideoxy-3'-Fluoroguanosine. Antimicrob. Agents Chemother. 50: 955-961 [Abstract] [Full Text]  
• Kim, J. W, Park, S. H, Louie, S. G (2006). Telbivudine: A Novel Nucleoside Analog for Chronic Hepatitis B. The Annals of Pharmacotherapy 40: 472-478 [Abstract] [Full Text]  
• Daftary, M. N., Goolsby, T., Farhat, F. (2006). An Update in the Management of Hepatitis B/HIV Coinfection. Journal of Pharmacy Practice 19: 31-36 [Abstract]  
• Lim, S. G., Ng, T. M., Kung, N., Krastev, Z., Volfova, M., Husa, P., Lee, S. S., Chan, S., Shiffman, M. L., Washington, M. K., Rigney, A., Anderson, J., Mondou, E., Snow, A., Sorbel, J., Guan, R., Rousseau, F., for the Emtricitabine FTCB-301 Study Group, (2006). A Double-blind Placebo-Controlled Study of Emtricitabine in Chronic Hepatitis B. Arch Intern Med 166: 49-56 [Abstract] [Full Text]  
• Lin, C.-c., Xu, C., Teng, A., Yeh, L.-T., Peterson, J. (2005). Pharmacokinetics of Pradefovir and PMEA in Healthy Volunteers After Oral Dosing of Pradefovir. J Clin Pharmacol 45: 1250-1258 [Abstract] [Full Text]  
• Menne, S., Cote, P. J., Korba, B. E., Butler, S. D., George, A. L., Tochkov, I. A., Delaney, W. E. IV, Xiong, S., Gerin, J. L., Tennant, B. C. (2005). Antiviral Effect of Oral Administration of Tenofovir Disoproxil Fumarate in Woodchucks with Chronic Woodchuck Hepatitis Virus Infection. Antimicrob. Agents Chemother. 49: 2720-2728 [Abstract] [Full Text]  
• Erhardt, A, Blondin, D, Hauck, K, Sagir, A, Kohnle, T, Heintges, T, Haussinger, D (2005). Response to interferon alfa is hepatitis B virus genotype dependent: genotype A is more sensitive to interferon than genotype D. Gut 54: 1009-1013 [Abstract] [Full Text]  
• Lau, G. K., Piratvisuth, T., Luo, K. X., Marcellin, P., Thongsawat, S., Cooksley, G., Gane, E., Fried, M. W., Chow, W. C., Paik, S. W., Chang, W. Y., Berg, T., Flisiak, R., McCloud, P., Pluck, N., the Peginterferon Alfa-2a HBeAg-Positive Chronic H, (2005). Peginterferon Alfa-2a, Lamivudine, and the Combination for HBeAg-Positive Chronic Hepatitis B. NEJM 352: 2682-2695 [Abstract] [Full Text]  
• Kanwal, F., Gralnek, I. M., Martin, P., Dulai, G. S., Farid, M., Spiegel, B. M.R. (2005). Treatment Alternatives for Chronic Hepatitis B Virus Infection: A Cost-Effectiveness Analysis. ANN INTERN MED 142: 821-831 [Abstract] [Full Text]  
• Lin, C.-C., Xu, C., Zhu, N., Lourenco, D., Yeh, L.-T. (2005). Single-Dose Pharmacokinetics and Metabolism of [14C]Remofovir in Rats and Cynomolgus Monkeys. Antimicrob. Agents Chemother. 49: 925-930 [Abstract] [Full Text]  
• Chan, H. L.-Y., Leung, N. W.-Y., Hui, A. Y., Wong, V. W.-S., Liew, C.-T., Chim, A. M.-L., Chan, F. K.-L., Hung, L. C.-T., Lee, Y.-T., Tam, J. S.-L., Lam, C. W.-K., Sung, J. J.-Y. (2005). A Randomized, Controlled Trial of Combination Therapy for Chronic Hepatitis B: Comparing Pegylated Interferon-{alpha}2b and Lamivudine with Lamivudine Alone. ANN INTERN MED 142: 240-250 [Abstract] [Full Text]  
• Erion, M. D., van Poelje, P. D., MacKenna, D. A., Colby, T. J., Montag, A. C., Fujitaki, J. M., Linemeyer, D. L., Bullough, D. A. (2005). Liver-Targeted Drug Delivery Using HepDirect Prodrugs. J. Pharmacol. Exp. Ther. 312: 554-560 [Abstract] [Full Text]  
• Perez-Roldan, F., Gonzalez-Carro, P., Villafanez-Garcia, M. C. (2005). Adefovir Dipivoxil for Chemotherapy-Induced Activation of Hepatitis B Virus Infection. NEJM 352: 310-311 [Full Text]  
• Aggarwal, R., Ranjan, P. (2004). Preventing and treating hepatitis B infection. BMJ 329: 1080-1086 [Full Text]  
• Delaney, W. E. IV, Yang, H., Miller, M. D., Gibbs, C. S., Xiong, S. (2004). Combinations of Adefovir with Nucleoside Analogs Produce Additive Antiviral Effects against Hepatitis B Virus In Vitro. Antimicrob. Agents Chemother. 48: 3702-3710 [Abstract] [Full Text]  
• Tacke, F., Gehrke, C., Luedde, T., Heim, A., Manns, M. P., Trautwein, C. (2004). Basal Core Promoter and Precore Mutations in the Hepatitis B Virus Genome Enhance Replication Efficacy of Lamivudine-Resistant Mutants. J. Virol. 78: 8524-8535 [Abstract] [Full Text]  
• Jacquard, A. C., Nassal, M., Pichoud, C., Ren, S., Schultz, U., Guerret, S., Chevallier, M., Werle, B., Peyrol, S., Jamard, C., Rimsky, L. T., Trepo, C., Zoulim, F. (2004). Effect of a Combination of Clevudine and Emtricitabine with Adenovirus-Mediated Delivery of Gamma Interferon in the Woodchuck Model of Hepatitis B Virus Infection. Antimicrob. Agents Chemother. 48: 2683-2692 [Abstract] [Full Text]  
• D'Souza, R., Foster, G. R (2004). Diagnosis and treatment of chronic hepatitis B. JRSM 97: 318-321 [Full Text]  
• Rivkin, A. M (2004). Adefovir Dipivoxil in the Treatment of Chronic Hepatitis B. The Annals of Pharmacotherapy 38: 625-633 [Abstract] [Full Text]  
• Ganem, D., Prince, A. M. (2004). Hepatitis B Virus Infection -- Natural History and Clinical Consequences. NEJM 350: 1118-1129 [Full Text]  
• Shen, Y., Zhukovskaya, N. L., Zimmer, M. I., Soelaiman, S., Bergson, P., Wang, C.-R., Gibbs, C. S., Tang, W.-J. (2004). Selective inhibition of anthrax edema factor by adefovir, a drug for chronic hepatitis B virus infection. Proc. Natl. Acad. Sci. USA 101: 3242-3247 [Abstract] [Full Text]  
• Sande, M. A., Ronald, A. R. (2004). Update in Infectious Diseases. ANN INTERN MED 140: 290-295 [Full Text]  
• Hochman, J. A., Balistreri, W. F. (2003). Chronic Viral Hepatitis: Always Be Current!. Pediatr. Rev. 24: 399-410 [Full Text]  
• De Clercq, E. (2003). Clinical Potential of the Acyclic Nucleoside Phosphonates Cidofovir, Adefovir, and Tenofovir in Treatment of DNA Virus and Retrovirus Infections. Clin. Microbiol. Rev. 16: 569-596 [Abstract] [Full Text]  
• Mukherjee, S., Marcellin, P., the Adefovir Dipivoxil 437 Study Group, (2003). Adefovir Dipivoxil for Hepatitis B e Antigen-Positive Chronic Hepatitis B. NEJM 348: 2468-2468 [Full Text]  
• (2003). Adefovir Dipivoxil: A New Treatment for Chronic Hepatitis B. JWatch Gastroenterology 2003: 3-3 [Full Text]  
• (2003). Adefovir: New Antiviral Agent for Treatment of Chronic Hepatitis B. JWatch Infect. Diseases 2003: 1-1 [Full Text]  
• (2003). New Treatment for Chronic Hepatitis B. JWatch General 2003: 1-1 [Full Text]  
• Hadziyannis, 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., the Adefovir Dipivoxil 438 Study Group, (2003). Adefovir Dipivoxil for the Treatment of Hepatitis B e Antigen-Negative Chronic Hepatitis B. NEJM 348: 800-807 [Abstract] [Full Text]  
• Mailliard, M. E., Gollan, J. L. (2003). Suppressing Hepatitis B without Resistance -- So Far, So Good. NEJM 348: 848-850 [Full Text]