The Liver Week 2016-6차.Hwp

Special Lecture 2. Special Lecture 2. Hepatitis C Virus: Next Generation of DAAs Mark Sulkowski Professor of Medicine Divisions of Infectious Diseases and Gastroenterology/Hepatology Johns Hopkins University School of Medicine Medical Director, Viral Hepatitis Center Johns Hopkins Hospital Baltimore Maryland USA In the current era, multiple HCV treatment regimens have been developed that are interferon-free and deliver high rates of HCV cure (> 95%) in most patient populations with treatment durations in the range of 12 weeks. In the context, the question can and should be asked: Is there a medical need for a next generation of DAAs. In short, the answer is that novel drugs and drug regimens are needed for certain patient populations including 1) Person who failed to achieve HCV cure with current DAAs need “salvage” regimens that can overcome HCV drug resistance associated variants (RAVs); 2) HCV genotype 3 for whom the treatment options are limited; 3) Persons for whom ribavirin is still recommended including those with HCV genotype 2 and some patients with cirrhosis. HCV NS3 Protease inhibitors. The first wave of HCV protease inhibitors – telaprevir, boceprevir and simeprevir – are not pangenotypic, lacking potent antiviral activity against HCV genotype 3. There are two protease inhibitors in phase 3 clinical trials that are once daily, potent, pangenotypic drugs: Voxilaprevir (VOX, GS-9857) and ABT-493. Voxilaprevir is being developed as a fixed-dose combination tablet including sofosbuvir and velpatasvir (a pangenotypic NS5A inhibitor). ABT-493 is being developed as a fixed-dose combination tablet including ABT-530 (a pangenotypic NS5A inhibitor). Both regimens are currently being evaluated in phase 3 clinical trials for treatment durations of 8 and 12 weeks in persons with all HCV genotypes and in those who failed DAA regimens. HCV NS5A inhibitors. Similar to protease inhibitors, many of the first wave of NS5A inhibitors lacked activity against HCV genotype 2 and 3 infection (the exception is daclatasvir). Velpatasvir is pangenotypic and has competed phase 3 trials in combination with sofosbuvir. The fixed-dose combination tablet given for a duration of 12 weeks led to HCV cure in > 99% of persons with HCV genotype 1, 2, 4, 5 and 6 infection and 95% of those with HCV genotype 3. This regimen is expected to be approved in the US and Europe in 2016. Other pangenotypic protease inhibitors in development include MK-8408 and the above-refer- enced ABT-530. While studies are ongoing, ABT-530 appears to be among the most active NS5A inhibitors against NS5A RAVs are position 93. HCV NS5B inhibitors. To date, sofosbuvir is the only approved nucleotide analogue NS5B inhibitor. Other DAAs in this class have been discontinued due to drug toxicity. In this context, MK3682 and AL-335 are currently in phase 2 clinical trials. MK3682 is being developed in combination with grazoprevir (NS3 protease inhibitor) and MK-8408 as a fixed dose combination tablet for the treatment of all HCV genotypes. Similarly, AL-335 is being tested in combination of AL-335, Odalasvir (NS5A inhibitor), and Simeprevir for the treatment of Genotype 1 chronic HCV infection. www.theliverweek.org 351.

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