title: Ledipasvir and sofosbuvir fixed-dose combination with and without ribavirin for 12 weeks in treatment-naive and previously treated Japanese patients with genotype 1 hepatitis C: an open-label, randomised, phase 3 trial.
abstract: BACKGROUND
  Compared with other countries, patients with chronic hepatitis C infection in Japan tend to be older, have more advanced liver disease, and are more likely to have been previously treated for hepatitis C. We aimed to assess the efficacy and safety of an all-oral, fixed-dose combination of the hepatitis C virus NS5A inhibitor ledipasvir and the NS5B nucleotide polymerase inhibitor sofosbuvir with and without ribavirin for 12 weeks in treatment-naive and previously treated Japanese patients with chronic genotype 1 hepatitis C virus infection.
  
  
  METHODS
  In this randomised, open-label study, we enrolled patients from 19 clinical Japanese centres. Patients were randomly assigned (1:1) to receive either ledipasvir (90 mg) and sofosbuvir (400 mg) or ledipasvir, sofosbuvir, and ribavirin (dosed according to the Japanese Copegus product label-ie, patients ≤60 kg received 600 mg daily, patients >60 kg to ≤80 kg received 800 mg daily, and patients >80 kg received 1000 mg daily) orally once daily for 12 weeks. After completion or early discontinuation of treatment, patients were followed up off-treatment for 24 weeks. Eligible patients were at least 20 years of age with chronic genotype 1 hepatitis C virus infection with serum hepatitis C virus RNA concentrations of at least 5 log10 IU/mL, creatinine clearance of at least 1·0 mL/s, and a platelet count of at least 50 × 10(9) per L. An interactive web response system was used to manage patient randomisation and treatment assignment. Randomisation was stratified by the presence or absence of cirrhosis for treatment-naive patients and stratified by presence or absence of cirrhosis and by previous treatment category (relapser or breakthrough, non-responder, or interferon-intolerant) for previously treated patients. Within each strata, patients were sequentially assigned to either treatment with ledipasvir-sofosbuvir or ledipasvir-sofosbuvir plus ribavirin in a 1:1 ratio with block size of 4. The primary endpoint was sustained virological response 12 weeks after completion of treatment (SVR12) assessed in all patients who were randomly assigned and received at least one dose of study drug; safety outcomes were assessed in all patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, number NCT01975675.
  
  
  RESULTS
  Between Oct 15, 2013 and Dec 13, 2013, 341 patients were randomly assigned to treatment groups and received at least one dose of study treatment. SVR12 was achieved in all 171 (100%) patients (83 of 83 treatment naive and 88 of 88 treatment experienced) receiving ledipasvir-sofosbuvir (95% CI 98-100) and 167 (98%) of 170 patients (80 of 83 treatment naive and 87 of 87 treatment experienced) receiving ledipasvir-sofosbuvir plus ribavirin (95% CI 95-100). Of the 76 patients with baseline NS5A resistant variants, 75 (99%) achieved SVR12. Two (1·2%) of 170 patients in the ledipasvir-sofosbuvir plus ribavirin group discontinued treatment because of adverse events. The most common adverse events were nasopharyngitis (50 [29·2%] of 171), headache (12 [7·0%] of 171), and malaise (nine [5·3%] of 171) in patients receiving ledipasvir-sofosbuvir; and nasopharyngitis (40 [23·5%] of 170), anaemia (23 [13·5%] of 170), and headache in those receiving ledipasvir-sofosbuvir and ribavirin (15 [8·8%] of 170).
  
  
  CONCLUSIONS
  Although existing regimens for the treatment of hepatitis C virus are effective for many patients, medical needs remain unmet, particularly in Japan where the population with hepatitis C virus genotype 1 is generally older and treatment-experienced, with advanced liver disease. The efficacy, tolerability, and absence of drug-drug interactions of ledipasvir-sofosbuvir suggest that it could be an important option for treatment of genotype 1 hepatitis C virus in Japanese patients.
  
  
  BACKGROUND
  Gilead Sciences.
authors: Kohnodai Hospital, National Center for Global Health and Medicine, Chiba, Japan. Electronic address: mmizokami@hospk.ncgm.go.jp.
authors: Masashi
authors: M
authors: Mizokami
authors: Chiba University, Chiba, Japan.
authors: Osamu
authors: O
authors: Yokosuka
authors: Osaka University, Osaka, Japan.
authors: Tetsuo
authors: T
authors: Takehara
authors: Hokkaido University, Hokkaido, Japan.
authors: Naoya
authors: N
authors: Sakamoto
authors: Kohnodai Hospital, National Center for Global Health and Medicine, Chiba, Japan.
authors: Masaaki
authors: M
authors: Korenaga
authors: Yamanashi Prefectural Hospital Organization, Yamanashi, Japan.
authors: Hitoshi
authors: H
authors: Mochizuki
authors: Akita City Hospital, Akita, Japan.
authors: Kunio
authors: K
authors: Nakane
authors: Hyogo College of Medicine, Hyogo, Japan.
authors: Hirayuki
authors: H
authors: Enomoto
authors: Okayama University, Okayama, Japan.
authors: Fusao
authors: F
authors: Ikeda
authors: National Center for Global Health and Medicine, Tokyo, Japan.
authors: Mikio
authors: M
authors: Yanase
authors: Ogaki Municipal Hospital, Gifu, Japan.
authors: Hidenori
authors: H
authors: Toyoda
authors: Juntendo University Shizuoka Hospital, Shizuoka, Japan.
authors: Takuya
authors: T
authors: Genda
authors: Shinshu University, Nagano, Japan.
authors: Takeji
authors: T
authors: Umemura
authors: National Hospital Organization Nagasaki Medical Center, Nagasaki, Japan.
authors: Hiroshi
authors: H
authors: Yatsuhashi
authors: Kurume University, Fukuoka, Japan.
authors: Tatsuya
authors: T
authors: Ide
authors: Mitsui Memorial Hospital, Tokyo, Japan.
authors: Nobuo
authors: N
authors: Toda
authors: Nihon University School of Medicine, Tokyo, Japan.
authors: Kazushige
authors: K
authors: Nirei
authors: Yamagata University, Yamagata, Japan.
authors: Yoshiyuki
authors: Y
authors: Ueno
authors: Gifu Municipal Hospital, Gifu, Japan.
authors: Yoichi
authors: Y
authors: Nishigaki
authors: Gilead Sciences, Foster City, CA, USA.
authors: Juan
authors: J
authors: Betular
authors: Gilead Sciences, Foster City, CA, USA.
authors: Bing
authors: B
authors: Gao
authors: Gilead Sciences KK, Tokyo, Japan.
authors: Akinobu
authors: A
authors: Ishizaki
authors: Gilead Sciences KK, Tokyo, Japan.
authors: Masa
authors: M
authors: Omote
authors: Gilead Sciences, Foster City, CA, USA.
authors: Hongmei
authors: H
authors: Mo
authors: Gilead Sciences, Foster City, CA, USA.
authors: Kim
authors: K
authors: Garrison
authors: Gilead Sciences, Foster City, CA, USA.
authors: Phillip S
authors: PS
authors: Pang
authors: Gilead Sciences, Foster City, CA, USA.
authors: Steven J
authors: SJ
authors: Knox
authors: Gilead Sciences, Foster City, CA, USA.
authors: William T
authors: WT
authors: Symonds
authors: Gilead Sciences, Foster City, CA, USA.
authors: John G
authors: JG
authors: McHutchison
authors: Musashino Red Cross Hospital, Tokyo, Japan.
authors: Namiki
authors: N
authors: Izumi
authors: Yamanashi Prefectural Hospital Organization, Yamanashi, Japan; Akita City Hospital, Akita, Japan.
authors: Masao
authors: M
authors: Omata
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000998:Antiviral Agents / Q000008:administration & dosage* / Q000009:adverse effects; D044466:Asian People; D001562:Benzimidazoles / Q000008:administration & dosage* / Q000009:adverse effects; D064420:Drug-Related Side Effects and Adverse Reactions / Q000453:epidemiology / Q000473:pathology; D005260:Female; D005449:Fluorenes / Q000008:administration & dosage* / Q000009:adverse effects; D005838:Genotype; D016174:Hepacivirus / Q000145:classification / Q000235:genetics / Q000302:isolation & purification; D019698:Hepatitis C, Chronic / Q000188:drug therapy* / Q000821:virology; D006801:Humans; D007564:Japan; D008297:Male; D008875:Middle Aged; D012254:Ribavirin / Q000008:administration & dosage / Q000009:adverse effects; D000069474:Sofosbuvir; D013997:Time Factors; D016896:Treatment Outcome; D014542:Uridine Monophosphate / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives*; D055815:Young Adult
chemical_list: D000998:Antiviral Agents; D001562:Benzimidazoles; D005449:Fluorenes; C586541:ledipasvir; D012254:Ribavirin; D014542:Uridine Monophosphate; D000069474:Sofosbuvir