title: HCV Drug Resistance Challenges in Japan: The Role of Pre-Existing Variants and Emerging Resistant Strains in Direct Acting Antiviral Therapy.
abstract: Sustained virological response (SVR) rates have increased dramatically following the approval of direct acting antiviral (DAA) therapies. While individual DAAs have a low barrier to resistance, most patients can be successfully treated using DAA combination therapy. However, DAAs are vulnerable to drug resistance, and resistance-associated variants (RAVs) may occur naturally prior to DAA therapy or may emerge following drug exposure. While most RAVs are quickly lost in the absence of DAAs, compensatory mutations may reinforce fitness. However, the presence of RAVs does not necessarily preclude successful treatment. Although developments in hepatitis C virus (HCV) therapy in Asia have largely paralleled those in the United States, Japan's July 2014 approval of asunaprevir plus daclatasvir combination therapy as the first all-oral interferon-free therapy was not repeated in the United States. Instead, two different combination therapies were approved: sofosbuvir/ledipasvir and paritaprevir/ritonavir/ombitasvir/dasabuvir. This divergence in treatment approaches may lead to differences in resistance challenges faced by Japan and the US. However, the recent approval of sofosbuvir plus ledipasvir in Japan and the recent submissions of petitions for approval of paritaprevir/ritonavir plus ombitasvir suggest a trend towards a new consensus on emerging DAA regimens.
authors.affiliation: Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8551, Japan. chayama@hiroshima-u.ac.jp.|Laboratory for Digestive Diseases, Center for Genomic Medicine, Institute of Physical and Chemical Research (RIKEN), Hiroshima 734-8551, Japan. chayama@hiroshima-u.ac.jp.|Liver Research Project Center, Hiroshima University, Hiroshima 734-8551, Japan. chayama@hiroshima-u.ac.jp.
authors.forename: Kazuaki
authors.initials: K
authors.lastname: Chayama
authors.affiliation: Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8551, Japan. nelsonhayes@hiroshima-u.ac.jp.|Liver Research Project Center, Hiroshima University, Hiroshima 734-8551, Japan. nelsonhayes@hiroshima-u.ac.jp.
authors.forename: C Nelson
authors.initials: CN
authors.lastname: Hayes
mesh_terms: D000998:Antiviral Agents / Q000494:pharmacology / Q000627:therapeutic use*; D017277:Drug Approval; D024882:Drug Resistance, Viral; D004359:Drug Therapy, Combination / Q000379:methods; D016174:Hepacivirus / Q000187:drug effects* / Q000235:genetics; D019698:Hepatitis C, Chronic / Q000188:drug therapy* / Q000821:virology*; D006801:Humans; D007564:Japan; D009154:Mutation
chemical_list: D000998:Antiviral Agents
keywords: NS5A inhibitor; direct-acting antivirals; hepatitis C; protease inhibitor; resistance; sustained viralresponse