Unfortunately, the intravenous mode of administration will ultimately limit the use of SIL in all-oral DAA combinations. The HCV p7 protein is a viroporin1 critical for the release of infectious virions. When its cation channel activity is pharmacologically blocked, virus production is significantly reduced.47 A number of HCV p7 inhibitors have been identified, such as amantadine, rimantadine,
long-alkylated iminosugar, and amiloride derivatives. selleck The in vitro sensitivity to HCV to these drugs is highly genotype-dependent, presumably because of the high sequence variability associated with the p7 genetic region. To date, none of these p7-directed agents has demonstrated any significant clinical activity. Another way to potentially limit acute as well as chronic HCV infection would be to prevent virus entry into the noninfected Lumacaftor mw cells. Ferroquine (FQ), a novel antimalarial currently undergoing clinical evaluation, has been reported recently to inhibit HCV entry in cell culture at the membrane fusion step.48 FQ-resistant HCV was selected with a single resistance-conferring mutation in the E1 envelope protein (S327A). FQ may
therefore represent a novel direct antiviral agent ready to be combined with other DAAs for all-oral therapy. Although there are still some concerns regarding how many of the anti-HCV drugs currently in development will actually hit the market, it is clear we are on the verge of a revolution in selleck chemical the treatment of chronic hepatitis C. This revolution, at least for the hard-to-cure HCV genotypes 1 and 4, is likely going to consist of a two- to three-step process that will ultimately lead us to the holy grail of an all-oral, pan-genotypic, IFN-free therapy. The first step forward in anti-HCV therapy will be the introduction of a second-wave
PI to be used in combination with PEG-IFN/RBV. This will be followed by NS5A and NS5B inhibitors to be used with PEG-IFN/RBV in triple therapy regimens or in quadruple therapy regimens in combination with a second-wave PI. Finally, several all-oral combinations will enter the market, likely becoming the standard of care first therapeutic option for all HCV genotypes. One of the main limitations of the first-wave PIs BOC and TVR is tolerability when they are used with PEG-IFN/RBV. This stems both from the induction of specific side effects as well as from the rather impractical assumption mode that both compounds require.49 These first-generation, first-wave PIs need to be taken every 7 to 9 hours with food, causing a significant pill burden that may lead to suboptimal adherence and suboptimal efficacy. First-generation, second-wave PIs such as simeprevir, faldaprevir, and ritonavir-boosted DNV will be able to bypass this issue, as they are being studied in phase 3 trials with once-daily dosing.