Compared to direct acting antivirals, which have a half-life of several hours, miravirsen has a long tissue half-life and prolonged antiviral activity. Miravirsen is rapidly cleared out of plasma, approximately within 1 h, and taken up into tissues. The highest concentration

of miravirsen is accomplished in liver and kidney tissue. However, the terminal elimination half-life of miravirsen is approximately 30 days. The slow elimination from the liver contributes to the sustained activity of miravirsen and could explain the prolonged effects of treatment. It was shown that miravirsen does not only target mature miR-122, but also suppresses the biogenesis of miR-122 at the primary- and precursor-miRNA levels in vitro (Gebert et al., 2014), which could contribute to this prolonged antiviral effect as well. In this context, the patient who remained HCV RNA negative for more than 7 months after find more the last dose of miravirsen Z VAD FMK is illustrative. The possibility of infection with a new virus or development of viral resistance was excluded by population sequencing. Sequence analyses showed no nucleotide changes in the 5′UTR nor amino acid differences in NS3, 5A and 5B regions. A limitation of this study is the small number of patients, which is due to the fact that

this study was the first to administer an anti-miR to humans. Furthermore, there was only one patient with fibrosis stage F4 included in the study, which made it difficult to evaluate the clinical effect of miR-122 inhibition in relation to cirrhosis. Another limitation of this study was that the extended follow-up was not part of the prospective study design, which led to a variation in follow-up duration. Nevertheless, the clinical efficacy on the long-term remains

of great importance regarding the potential risk of HCC development. In fact, the theoretical risk to induce HCC by miR-122 suppression is the main reason why the Food and Drug Administration now requests a total follow-up duration of five years for patients treated with anti-miR-122 therapy. Since the initial follow-up Dolichyl-phosphate-mannose-protein mannosyltransferase period of these patients was 18 weeks, this study provides important additional clinical and safety information of the first patients treated with anti-miR therapy. The therapeutic field for HCV is changing quickly with the ongoing development and recent registration of several DAAs. This study was the first to evaluate the long-term safety and efficacy data of chronic hepatitis C patients treated with an anti-miR-122. Currently a regimen of 12 weeks monotherapy with miravirsen is being evaluated in clinical trials. The potential and safety of miR-122 inhibition as a therapeutic target for HCV eradication needs to be further examined.