HCV Council--critical appraisal of data: recommendations for clinical practice in a rapidly evolving therapeutic landscape.

BACKGROUND & AIMS: HCV Council 2014, like its predecessor HCV Council 2011, assembled leading clinicians and researchers in the field of hepatitis C to critically evaluate current data regarding best practices for managing patients with chronic hepatitis C virus (HCV). METHODS: Clinical practice statements were developed that reflect the areas of potential controversy with high clinical impact. Faculty members were responsible for reviewing the literature to support or reject these statements. After a review and comprehensive discussion of the data, the HCV Council faculty voted on the nature of the evidence and the level of support for each statement. RESULTS: The results of the detailed analysis with expert opinion are summarized in this article. CONCLUSION: Numerous questions regarding optimal management of certain populations and clinical scenarios remain unanswered. The discussion in the article provides a summary of evidenced-based expert opinion that may help guide clinicians as additional information is developed.

[Significance of hepatitis C virus baseline polymorphism during the antiviral therapy]. / A hepatitis C-vírus-bázispolimorfizmus jelentosége a kezelésben.

The treatment of chronic hepatitis C has developed significantly during the last 25 years. In patients with genotype 1 infection 40-50% sustained virologic response could be achieved using pegylated interferon and ribavirin dual combination, which could be increased significantly with the introduction of direct acting antivirals. Three major groups of direct acting antivirals are known, which directly inhibit different phases of viral life cycle, by inhibiting the function of several non-structural proteins (NS3/4A protease, NS5A protein and NS5B polymerase). Due to the rapid replication rate of hepatitis C virus and the error-prone NS5B polymerase activity, mutant virions are generated, which might have reduced susceptibility to direct acting antiviral therapy. Since these resistance associated variants might exist before the antiviral therapy, they are still able to replicate during the direct acting antiviral treatment. Due to this selection pressure, the resistant virus will replace the wild type. This was especially detected during monotherapy, therefore, the first generation of direct acting antivirals have been combined with pegylated interferon and ribavirin, while recently interferon-free combinations are being developed including 2 or 3 direct acting antivirals. Using the first generation protease inhibitors boceprevir and telaprevir, it could have been seen, that the rate of resistance associated variants is higher and the therapeutic outcome is worse in patients with hepatitis C virus genotype 1a, than in 1b. Similar phenomenon was seen with the second generation of NS3/4A protease inhibitors as well as with NS5A or NS5B polymerase. This is due to the lower genetic barrier to resistance, ie. usually fewer mutations are enough for the emergence of resistance in genotype 1a. The selection of resistance associated variants is one of the most important challenges during the interferon-free therapy.

Pharmacokinetics, Food Effect, Ketoconazole Interaction, and Safety of JTK-853, a Novel Nonnucleoside HCV Polymerase Inhibitor, After Ascending Single and Multiple Doses in Healthy Subjects.

Pharmacokinetics, safety, and tolerability of JTK-853, a novel HCV polymerase inhibitor, were evaluated in single and multiple ascending dose (SAD, MAD) studies, with food- and ketoconazole-related effects on exposure to JTK-853 and its active (CYP3A4 mediated) metabolite M2. JTK-853 was safe and well tolerated in both studies. In the SAD study, at doses >1600 mg (with standard breakfast [SBF]), JTK-853 exposure did not increase further, was substantially higher (AUCinf increase: 3- to 8-fold) with SBF (vs fasted), with a moderate increase in AUCinf (approximately 1.5-fold [1600 mg]) with a high-fat breakfast (vs SBF). In the SAD study (400-1600 mg, SBF), mean effective half-life (t1/2(eff) ) of JTK-853 was 8.3 to 10.9 hours, and 20.3 to 27.3 hours in the MAD study (twice daily dosing, fed condition), with 2- to 3-fold accumulation in exposure (AUCtau ). At steady-state, AUCtau increased dose proportionally, and was approximately 2-fold higher with ketoconazole coadministration. Metabolite M2 (equipotent to JTK-853 in vitro) did not contribute significantly to parent drug exposure and decreased with increase in dose, repeated dosing, and ketoconazole coadministration. Trial simulation-based ratios (n = 1000/dose level) of trough JTK-853 plasma concentrations to the in vitro EC90 for HCV genotype 1b were assessed for dose selection in a separate proof-of-concept study in patients. The studies enabled delineation of key drug attributes for further assessments in the target population.