I-105 Advances in the treatment of chronic HCV infection with direct acting antivirals

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Next generation of DAAs are aimed at (1) Person who need “salvage” regimens that can overcome HCV drug resistance associated variants (RAVs); (2) HCV genotype 3; (3) Persons for whom ribavirin is still recommended. HCV NS3 Protease inhibitors. The first wave of HCV protease inhibitors were 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). 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-referenced 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 and MK-8408 as a fixed dose combination tablet for the treatment of all HCV genotypes. Similarly, AL-335 is being tested in combination with Odalasvir (NS5A inhibitor), and Simeprevir for the treatment of Genotype 1 chronic HCV infection.

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