We thank Drs. Dahari and Perelson for their interesting comment which allows us to discuss the mathematical model as an interpretation of the antiviral effects of interferon (IFN) and newly developed antivirals.
DEBIO-025 is a potent cyclophilin inhibitor that suppresses hepatitis C virus (HCV) replication in the replicon system and chimeric mice model.1, 2 In a recent clinical trial in patients coinfected with HCV-human immunodeficiency virus (HIV) in Poland, mean HCV viral load decreased 3.6 log10 after 2 weeks treatment with DEBIO-025 1200 mg BID monotherapy.3 Recently developed kinetic models of HCV RNA decay induced by IFN therapy, which were formulated by close monitoring of HCV RNA and aminotransferase levels before and after the start of IFN treatment, provide a useful means of assessing IFN treatment.4 However, these are not sufficient to assess the effects of new compounds alone or in combination therapy.
Viral decay during DEBIO-025 monotherapy in coinfected patients fits the biphasic viral kinetic model.5 However, in chimeric mice infected with genotype 1b viral decay was not biphasic,2 because it lacked the second phase decline, probably because these SCID (severe combined immunodeficient) mice lack both T cells and B cells. In this chimeric mouse model, serum alanine aminotransferase and albumin levels do not change with treatment.2 This is possibly due to poor elimination of infected hepatocytes by the host-immune response, but we do not have any data on human hepatocyte death or turnover rate in our chimeric mice. Therefore, we cannot verify the validity of the current HCV dynamic model in which short-term cell death is the central premise.
As Dahari and Perelson mentioned, IFN induces biphasic decay of HCV RNA without cell death in the replicon system. Therefore, we believe that the second phase of viral decay is not necessary accompanied by cell death. We agree with the refined recent model.6 Generally speaking, intracellular HCV RNA is divided into 2 components based on differences in IFN sensitivity, and decay of HCV RNA may show a biphasic pattern. We also should consider the pharmacokinetics and pharmacodynamics of new compounds, especially if they have unique biological and pharmacological effects, in order to construct an even more accurate predictive model of HCV RNA decay.