Yalan Wang1, Florian Van Boemmel2, Swantje Martens1, Thomas Berg2, Stefan Zeuzem1, Eva Herrmann3
1 J. W. Goethe University Hospital, Frankfurt/M, Germany, 2 Charité, Campus Virchow, Humboldt University of Berlin, Germany, 3 Saarland University, Homburg/Saar, Germany
Background : Recently, treatment response to the nucleotide analogue Tenofovir disoproxil fumarate (TDF) was analyzed in patients developing genotypic resistance against lamivudine and also adefovir dipivoxil (ADV) in previous treatments. Even so cross-resistance of TDF and ADV has been reported, treatment with high-dose TDF showed a moderate and stable antiviral efficacy but also a selection of resistant variants. Here, we propose a general multi-variant model of viral kinetics.
Methods : We propose a differential equation system to describe the dynamics of wild-type as well as resistant variants with single and double mutants. The model uses different fitness parameters and treatment efficacies for each variant whereas further viral kinetic parameters such as viral clearance, infected-cell loss and de-novo infection rates are identical for all variants. The model also accounts for a shared and limited HBV replication space. It is used to fit HBV DNA kinetics and serial sequencing data in 10 patients treated with TDF.
Results : Overall, kinetics seems to be triphasic, a relatively fast first phase of viral decline during the first week, a slower but still declining phase and a flat phase when resistant variants became dominant. Only 2 of 10 patients had undetectable viral load after 12 months of treatment. Treatment efficacy factors and relative fitness of observed ADV resistant variants showed a high variation (50%-92% and 0.81-0.97, respectively) between different variants in each patient.
Conclusions : The multi-variant model can be successfully applied to describe the anti-viral activity of TDF and viral kinetics for treatment of ADV resistance.