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Dr. Moriguchi and colleagues raise two issues in their letter. The first is related to the statins (simvastatin and mevastatin) that were used in our in vitro combination studies. We agree with Dr. Moriguchi that pitavastatin possesses the strongest anti–hepatitis C virus (HCV) activity among the statins tested in their replicon assay.1 Their suggestion to evaluate the in vitro antiviral effects of combinations of HCV polymerase and protease inhibitors with pitavastatin is therefore interesting and appropriate. However, it should be noted that pitavastatin cannot be easily obtained, for which reason we did not include this compound in our study. The aim of our study was to demonstrate a proof-of-concept2; inclusion of pitavastatin would very likely have resulted in similar data and/or the same conclusions.

The second issue was related to the evaluation of the toxicity of combination therapies. We agree that human induced pluripotent stem cells (iPSCs) may provide an interesting and useful tool to assess the potential toxicity of the combination therapy. However, we are not aware of any other publication in which (novel) inhibitors of HCV replication were reported, that made use of this iPSCs to assess potential toxicity of such compounds. As was recently reviewed by Heng and colleagues, there remain several important questions regarding the use of iPSCs in toxicology (screening) assays.3 It is currently unknown how the epigenetic state of reprogrammed iPSCs compares with that of human embryonic stem cells derived from “normal” human blastocyst-stage embryos. Moreover, the derivation of iPSCs entails permanent genetic modification to somatic cells, due to the use of viral transduction of recombinant DNA. Integration of recombinant DNA within the genome of iPSCs might cause these cells, or their differentiated progenies, to behave differently from normal unmodified human cells, in particular when exposed to toxic challenges.

References

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  • 1
    Ikeda M, Kato N. Life style-related diseases of the digestive system: cell culture system for the screening of anti-hepatitis C virus (HCV) reagents: suppression of HCV replication by statins and synergistic action with interferon. J Pharmacol Sci 2007; 105: 145150.
  • 2
    Delang L, Paeshuyse J, Vliegen I, Leyssen P, Obeid S, Durantel D, et al. Statins potentiate the in vitro anti-hepatitis C virus activity of selective hepatitis C virus inhibitors and delay or prevent resistance development. HEPATOLOGY 2009; 50: 616.
  • 3
    Heng BC, Richards M, Shu Y, Gribbon P. Induced pluripotent stem cells: a new tool for toxicology screening? Arch Toxicol 2009; 83: 641644.

Leen Delang*, Johan Neyts*, * Department of Microbiology and Immunology, Katholieke Universiteit Leuven, Leuven, Belgium.