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Selection of multiresistant hepatitis B virus during sequential nucleoside-analogue therapy
1Public Health Laboratory Service Antiviral Susceptibility Reference Unit, Divisions of Medical Sciences, University of Birmingham Medical School, Edgbaston, Birmingham, United Kingdom.
The Journal of Infectious Diseases
|February 11, 2000
Summary
Hepatitis B virus (HBV) drug resistance to lamivudine involves specific mutations. Adding famciclovir to lamivudine therapy did not suppress HBV in resistant patients, highlighting challenges in treating drug-resistant infections.
Area of Science:
- Hepatology
- Virology
- Pharmacology
Background:
- Hepatitis B virus (HBV) drug resistance to lamivudine is linked to polymerase gene mutations at position 550 (Group 1: M550V/L526M; Group 2: M550I).
- Group 2 mutations (M550I) were not previously associated with famciclovir resistance, suggesting potential efficacy of combination therapy.
Purpose of the Study:
- To evaluate the effect of adding famciclovir to lamivudine therapy in patients with lamivudine-resistant HBV infection.
- To investigate the emergence of multidrug-resistant HBV variants under combination therapy.
Main Methods:
- Quantitative polymerase chain reaction (qPCR) to measure HBV load.
- Polymerase gene sequencing of serum HBV DNA.
- Cloning experiments to identify pre-existing viral variants.
Main Results:
- No significant decline (>1 log10) in HBV viral load was observed in patients receiving lamivudine/famciclovir combination therapy.
- Continuous evolution of the HBV polymerase gene was detected, correlating with virologic resistance to both drugs.
- Cloning revealed that multidrug-resistant HBV variants existed as minority species before famciclovir addition.
Conclusions:
- HBV resistance to lamivudine monotherapy involves complex viral mixtures that limit the effectiveness of subsequent nucleoside-analogue therapies.
- The pre-existence of resistant variants complicates treatment strategies.
- First-line potent combination therapy might be a strategy to reduce the emergence of HBV drug resistance.