final program.qxd - Parallels Plesk Panel

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Primary Resistance of a Novel Hepatitis B Virus Variant to Adefovir
Oliver Schildgen PhD 1* , Hueseyin Sirma MD 5* , Anneke Funk PhD 5 , Cynthia Olotu 5 , Ulrike
C. Wend 2 , Heinz Hartmann MD 3 , Martin Helm 4 , Jürgen K. Rockstroh MD 1 , Wulf R.
Willems MD 2 , Hans Will PhD 5§ , Wolfram H. Gerlich PhD 2§
1. Institute of Medical Microbiology and Immunology and Department of Medicine I
University of Bonn, Germany
2. Institute of Medical Virology, University of Giessen, Germany
3. Practice for Gastroenterology and Hepatology, Herne, Germany
4. Practice Abelein/Helm, Nuremberg, Germany
5. Heinrich-Pette-Institut, Hamburg, Germany
* The first two authors contributed equally to this work.
§ The last two authors contributed equally to this work.
Introduction
We observed three HBV-infected patients that displayed no decrease of the viral load
under therapy with adefovir; a therapy switch to tenofovir resulted in a significant drop of
the viral load.
Methods
HBV DNA was isolated and the DNA polymerase gene was amplified by PCR for
sequencing. Sequencing was carried out using the BigDye terminator reaction.
Genotyping and identification of mutations were performed with the INNO-LiPA assay and
by sequencing of PCR products. The relevance of the mutation rtI233V for Adefovir
resistance was tested by site-directed mutagenesis of standard HBV genotype D wt and
transfection of a hepatoma cell line.
Results
Adefovir was ineffective in all three patients. Sequencing analysis of all HBV strains
analysed from the patients revealed no amino acid exchange at the Adefovir-resistance
positions rt236 or rt181. All patients were infected with HBV genotype D, accompanied
HBsAg subtype ayw4, and displayed a unique mutation rtI233V. The resistance to
adefovir mediated by this mutation was confirmed by the in vitro resistance testing.
Replication of the transfected variant was not inhibited by Adefovir.
Conclusion
Based on our present observations and our recent data (Schildgen et al.; AIDS
18(17):2325-7) we conclude, that polymorphisms like rtI233V in the polymerase/reversetranscriptase
domain aa 215 to aa 236 mediate adefovir resistance. In contrast to the
known resistance mutations at rt181 or rt236, the variant rtI233V exists before therapy.
Based on our in vivo observations, we strongly recommend to consider a therapy change
to tenofovir whenever this variant is observed.
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