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Emergence of cross-resistant herpes simplex virus following topical drug therapy in rabbit keratitis
C Fardeau1, M Langlois, B Mathys
1Unité de Recherches d'Ophtalmologie, INSERM U 86, Hôtel-Dieu, Paris, France.
Abstract:
The acquisition of drug resistance in vivo was investigated by 7 serial passages (from P0 to P7) of herpes simplex virus (HSV-1) in rabbit cornea treated with either IUdR (idoxuridine), IDC (idoxycytidine), ACV (acyclovir), TFT (trifluridine), or Ara A (adenine arabinoside). Therapeutic failure was acquired gradually: at P3 for IUdR, at P4 for ACV and at P5 for TFT. At P7, viral thymidine kinase (TK) activity was reduced to 5.6% of the parental strain for IUdR, to 7.5% for ACV and to 4.6% for TFT treatment. No signs of clinical unresponsiveness occurred with IDC or Ara A. The in vitro determination of antiviral drug sensitivity performed by the dye-uptake assay on HSV isolates at each passage showed a correlation between the increase in the 50% effective dose (ED50) and the increase of ulcer area grade at each passage under antiviral drug (p less than 0.1). Both IUdR- and TFT-resistant HSV1 developed cross-resistances to TK dependent drugs. However ACV-resistant HSV1 did not show cross-resistance to other antiviral TK dependent drugs. The acquisition of the cross-resistances is discussed, and the practical implications in case of therapeutic failures are suggested.
Insights
Herpes simplex virus (HSV-1) developed drug resistance during serial passage, with trifluridine and idoxuridine showing gradual therapeutic failure and reduced viral thymidine kinase activity. Acyclovir-resistant HSV-1 did not exhibit cross-resistance to other TK-dependent drugs.
Area of Science:
- Virology
- Pharmacology
- Ophthalmology
Background:
- Herpes simplex virus (HSV-1) infections can lead to therapeutic challenges.
- The development of antiviral drug resistance is a significant concern in managing HSV-1.
- Understanding resistance mechanisms is crucial for effective treatment strategies.
Purpose of the Study:
- To investigate the in vivo acquisition of drug resistance in HSV-1.
- To evaluate the development of resistance to idoxuridine (IUdR), acyclovir (ACV), trifluridine (TFT), idoxycytidine (IDC), and adenine arabinoside (Ara A).
- To assess cross-resistance patterns among antiviral drugs.
Main Methods:
- Serial passage of HSV-1 in rabbit corneas treated with antiviral drugs (IUdR, IDC, ACV, TFT, Ara A) for 7 passages (P0-P7).
- Monitoring therapeutic failure and clinical unresponsiveness.
- Assessing viral thymidine kinase (TK) activity at P7.
- In vitro drug sensitivity testing using a dye-uptake assay to determine the 50% effective dose (ED50).
Main Results:
- Therapeutic failure occurred gradually: by P3 for IUdR, P4 for ACV, and P5 for TFT.
- Viral TK activity significantly decreased in IUdR-, ACV-, and TFT-treated groups by P7.
- No clinical unresponsiveness was observed with IDC or Ara A.
- A correlation was found between increased ED50 and increased ulcer grade.
- IUdR- and TFT-resistant HSV-1 developed cross-resistances to TK-dependent drugs, but ACV-resistant HSV-1 did not.
Conclusions:
- HSV-1 can acquire resistance to antiviral drugs like IUdR, ACV, and TFT through serial passage.
- Reduced viral TK activity is associated with resistance development.
- Cross-resistance patterns vary, with ACV-resistant strains showing unique behavior.
- Findings have implications for managing therapeutic failures in HSV-1 infections.