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Antimicrobial Agents and Chemotherapy, November 2008, p. 4069-4071, Vol. 52, No. 11
0066-4804/08/$08.00+0     doi:10.1128/AAC.00078-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Potential for Hepatitis C Virus Resistance to Nitazoxanide or Tizoxanide{triangledown}

Brent E. Korba,1* Menashe Elazar,2 Ping Lui,2 Jean-François Rossignol,2,3 and Jeffrey S. Glenn2

Division of Molecular Virology and Immunology, Department of Microbiology and Immunology, Georgetown University Medical Center, Washington, DC,1 Division of Gastroenterology and Hepatology, Department of Medicine, Stanford University School of Medicine, Palo Alto, California,2 The Romark Institute for Medical Research, Tampa, Florida3

Received 18 January 2008/ Returned for modification 25 February 2008/ Accepted 7 August 2008

Nitazoxanide and its primary metabolite, tizoxanide, inhibit hepatitis C virus (HCV) replication in HCV replicon systems. To study the potential for resistance, we subjected Huh7 cells harboring HCV replicons to serial passage in 250 µM G418 and increasing concentrations of nitazoxanide or tizoxanide. Passage of the replicon-containing cell lines in either compound resulted in increases in the 50% effective concentrations (EC50s) (7- to 13-fold), EC90s (14- to 36-fold), and 50% cytotoxic concentrations (2- to 4-fold) of both compounds. Serial passage in either compound did not alter the susceptibility of HCV replicons to ribavirin or 2'-C-methylcytidine. Interestingly, serial passage in nitazoxanide or tizoxanide resulted in increased sensitivity to alpha interferon 2b: EC50s and EC90s were reduced three- and eightfold, respectively. Replicons isolated from these cell lines had no greater ability to confer tizoxanide resistance, or increased susceptibility to alpha interferon, than replicons isolated from the parental cell line that had not previously been exposed to nitazoxanide or tizoxanide. These findings are indicative of a cell-mediated activity differing from that of other anti-HCV drugs but complementary with interferon and are consistent with the enhanced response rates observed clinically when nitazoxanide is combined with pegylated interferon therapy. Finally, unlike data for other compounds in advanced clinical development for HCV, these data are consistent with resistance in HCV replicon-containing cell lines conferred by changes in the host and not by mutations in the virus.

* Corresponding author. Mailing address: Georgetown University Medical Center, Department of Microbiology and Immunology, 3900 Reservoir Road, NW, Medical-Dental Building, Room SW319, Washington, DC 20057. Phone: (202) 687-8627. Fax: (202) 687-1800. E-mail: korbabe{at}georgetown.edu

{triangledown} Published ahead of print on 18 August 2008.

Antimicrobial Agents and Chemotherapy, November 2008, p. 4069-4071, Vol. 52, No. 11
0066-4804/08/$08.00+0     doi:10.1128/AAC.00078-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.





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