title: Dual therapy with the nonstructural protein 5A inhibitor, daclatasvir, and the nonstructural protein 3 protease inhibitor, asunaprevir, in hepatitis C virus genotype 1b-infected null responders.
abstract: Patients with chronic hepatitis C virus (HCV) infection and previous null response to pegylated interferon (Peg-IFN) and ribavirin (RBV) have limited therapeutic options. HCV genotype 1 is the most common worldwide and the most difficult to treat; genotype 1b is the most common subtype of genotype 1 outside North America. The enhanced antiviral activity achieved by combining two direct-acting antiviral (DAA) agents may improve clinical outcomes. This open-label, phase IIa study included 10 patients with chronic HCV genotype 1b infection and previous null response (<2 log(10) reduction in HCV RNA after 12 weeks) to Peg-IFN and RBV. Patients received dual DAA treatment for 24 weeks with the nonstructural protein 5A replication complex inhibitor, daclatasvir (60 mg once-daily), and the nonstructural protein 3 protease inhibitor, asunaprevir (initially 600 mg twice-daily, then subsequently reduced to 200 mg twice-daily). The primary efficacy endpoint was the proportion of patients with sustained virologic response (SVR) at 12 weeks post-treatment (SVR(12) ). Nine patients completed 24 weeks of treatment; 1 patient discontinued treatment after 2 weeks. In the 9 patients who completed the full course of treatment, HCV RNA was undetectable at week 8 and remained undetectable through the end of treatment; all 9 patients achieved SVR(12) and SVR(24) . HCV RNA also remained undetectable post-treatment in the patient who discontinued after 2 weeks. There was no viral breakthrough. Diarrhea and headache, generally mild, were the most common adverse events; transaminase elevations were reported in 3 patients, but did not result in discontinuation.
  
  
  CONCLUSIONS
  Dual therapy with daclatasvir and asunaprevir, without Peg-IFN and RBV, can achieve high SVR rates in difficult-to-treat patients with HCV genotype 1b infection and previous null response to Peg-IFN and RBV.
authors: Hiroshima University, Hiroshima, Japan. chayama@hiroshima-u.ac.jp
authors: Kazuaki
authors: K
authors: Chayama
authors: Shoichi
authors: S
authors: Takahashi
authors: Joji
authors: J
authors: Toyota
authors: Yoshiyasu
authors: Y
authors: Karino
authors: Kenji
authors: K
authors: Ikeda
authors: Hiroki
authors: H
authors: Ishikawa
authors: Hideaki
authors: H
authors: Watanabe
authors: Fiona
authors: F
authors: McPhee
authors: Eric
authors: E
authors: Hughes
authors: Hiromitsu
authors: H
authors: Kumada
mesh_terms: D000328:Adult; D000368:Aged; D000998:Antiviral Agents / Q000009:adverse effects / Q000627:therapeutic use*; D002219:Carbamates; D003967:Diarrhea / Q000139:chemically induced / Q000453:epidemiology; D004359:Drug Therapy, Combination; D005260:Female; D005838:Genotype; D006261:Headache / Q000139:chemically induced / Q000453:epidemiology; D016174:Hepacivirus / Q000235:genetics*; D006526:Hepatitis C / Q000188:drug therapy* / Q000208:ethnology; D006801:Humans; D007093:Imidazoles / Q000009:adverse effects / Q000627:therapeutic use*; D015994:Incidence; D016898:Interferon-alpha / Q000627:therapeutic use; D007546:Isoquinolines / Q000009:adverse effects / Q000627:therapeutic use; D007564:Japan; D008297:Male; D008875:Middle Aged; D011092:Polyethylene Glycols / Q000627:therapeutic use; D011480:Protease Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*; D011759:Pyrrolidines; D011994:Recombinant Proteins / Q000627:therapeutic use; D012254:Ribavirin / Q000627:therapeutic use; D013449:Sulfonamides / Q000009:adverse effects / Q000627:therapeutic use; D017211:Treatment Failure; D016896:Treatment Outcome; D014633:Valine / Q000031:analogs & derivatives; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors*
chemical_list: D000998:Antiviral Agents; D002219:Carbamates; D007093:Imidazoles; D016898:Interferon-alpha; D007546:Isoquinolines; D011480:Protease Inhibitors; D011759:Pyrrolidines; D011994:Recombinant Proteins; D013449:Sulfonamides; D017361:Viral Nonstructural Proteins; D011092:Polyethylene Glycols; D012254:Ribavirin; D014633:Valine; C549273:daclatasvir; C100416:peginterferon alfa-2a; C571889:asunaprevir