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Potential for hepatitis C virus resistance to nitazoxanide or tizoxanide

Brent E Korba1, Menashe Elazar, Ping Lui

  • 1Department of Microbiology and Immunology, Georgetown University Medical Center, Washington, DC 20057, USA. korbabe@georgetown.edu

Antimicrobial Agents and Chemotherapy
|August 20, 2008
PubMed

Insights

Nitazoxanide and tizoxanide increase resistance to themselves but enhance sensitivity to interferon in hepatitis C virus (HCV) cell models. Resistance appears cell-mediated, not virus-mutated, suggesting synergy with interferon therapy.

Area of Science:

  • Virology
  • Drug Resistance Studies
  • Hepatitis C Virus (HCV) Research

Background:

  • Nitazoxanide and its metabolite tizoxanide demonstrate inhibitory effects on hepatitis C virus (HCV) replication.
  • Understanding drug resistance mechanisms is crucial for developing effective HCV therapies.

Purpose of the Study:

  • To investigate the potential for drug resistance development to nitazoxanide and tizoxanide in HCV replicon systems.
  • To explore the impact of serial passage in these compounds on HCV susceptibility to other antiviral agents and interferon.

Main Methods:

  • HCV replicon-containing Huh7 cells were subjected to serial passage with increasing concentrations of nitazoxanide or tizoxanide.
  • Antiviral susceptibility (EC50, EC90) and cytotoxicity (CC50) were assessed for nitazoxanide, tizoxanide, ribavirin, 2'-C-methylcytidine, and interferon-alpha 2b.
  • HCV replicons were isolated and characterized from resistant cell lines.

Main Results:

  • Serial passage led to a 7- to 36-fold increase in EC50 and EC90 for nitazoxanide and tizoxanide, indicating developed resistance.
  • HCV susceptibility to ribavirin and 2'-C-methylcytidine remained unchanged.
  • A 3- to 8-fold increase in sensitivity to interferon-alpha 2b was observed after serial passage.
  • Isolated replicons did not exhibit increased resistance or interferon sensitivity compared to parental lines, suggesting cell-mediated resistance.

Conclusions:

  • Nitazoxanide and tizoxanide resistance in HCV cell models is likely cell-mediated, not due to viral mutations.
  • This cell-mediated resistance mechanism differs from other anti-HCV drugs but is complementary to interferon therapy.
  • Findings support the clinical observation of enhanced response rates when nitazoxanide is combined with pegylated interferon for HCV treatment.

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