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Antimicrobial Agents and Chemotherapy, January 2003, p. 324-336, Vol. 47, No. 1
0066-4804/03/$08.00+0     DOI: 10.1128/AAC.47.1.324-336.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Comparison of Anti-Hepatitis B Virus Activities of Lamivudine and Clevudine by a Quantitative Assay

Ayman M. Abdelhamed,1 Colleen M. Kelley,1 Thomas G. Miller,1 Phillip A. Furman,2 Edward E. Cable,1 and Harriet C. Isom1,3*

Department of Microbiology and Immunology,1 Department of Pathology, Milton S. Hershey Medical Center, The Penn State College of Medicine, Hershey, Pennsylvania 17033,3 Triangle Pharmaceuticals, Durham, North Carolina 277072

Received 14 February 2002/ Returned for modification 7 May 2002/ Accepted 17 October 2002

In this study, we used a quantitative assay to measure the concentration-dependent effects of antivirals on extracellular hepatitis B virus (HBV) DNA as well as on different cytoplasmic and nuclear forms of HBV DNA that participate in HBV replication. HBV recombinant baculovirus, which efficiently delivers the HBV genome to HepG2 cells, was used for this study because (i) antivirals can be administered prior to initiation of HBV infection or after HBV infection and (ii) sufficiently high HBV replication levels are achieved that HBV covalently closed circular (CCC) DNA can be easily detected and individual HBV DNA species can be quantitatively analyzed separately from total HBV DNA. The results showed that the levels of HBV replicative intermediate and extracellular DNA decreased in a concentration-dependent fashion following antiviral treatment. The 50% effective concentration (EC50) and EC90 values and the Hill slopes differed for the different HBV DNA species analyzed. The data clearly indicated that (i) nuclear HBV DNAs are more resistant to antiviral therapy than cytoplasmic or extracellular HBV DNAs and (ii) nuclear HBV CCC DNA is more resistant than the nuclear relaxed circular form. This report presents the first in vitro comparison of the effects of two antivirals administered prior to initiation of HBV infection and the first thorough in vitro quantitative study of concentration-dependent antiviral effects on HBV CCC DNA.

* Corresponding author. Mailing address: Milton S. Hershey Medical Center, The Penn State College of Medicine, 500 University Dr., P.O. Box 850, Hershey, PA 17033. Phone: (717) 531-8609. Fax: (717) 531-4133. E-mail: hisom{at}psu.edu.

Antimicrobial Agents and Chemotherapy, January 2003, p. 324-336, Vol. 47, No. 1
0066-4804/03/$08.00+0     DOI: 10.1128/AAC.47.1.324-336.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Starkey, J. L., Chiari, E. F., Isom, H. C. (2009). Hepatitis B virus (HBV)-specific short hairpin RNA is capable of reducing the formation of HBV covalently closed circular (CCC) DNA but has no effect on established CCC DNA in vitro. J. Gen. Virol. 90: 115-126 [Abstract] [Full Text]  
  • Gao, W., Hu, J. (2007). Formation of Hepatitis B Virus Covalently Closed Circular DNA: Removal of Genome-Linked Protein. J. Virol. 81: 6164-6174 [Abstract] [Full Text]  
  • Heipertz, R. A. Jr., Miller, T. G., Kelley, C. M., Delaney, W. E. IV, Locarnini, S. A., Isom, H. C. (2007). In Vitro Study of the Effects of Precore and Lamivudine-Resistant Mutations on Hepatitis B Virus Replication. J. Virol. 81: 3068-3076 [Abstract] [Full Text]  


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