title: Ombitasvir plus paritaprevir plus ritonavir with or without ribavirin in treatment-naive and treatment-experienced patients with genotype 4 chronic hepatitis C virus infection (PEARL-I): a randomised, open-label trial.
abstract: BACKGROUND
  Hepatitis C virus (HCV) genotype 4 accounts for about 13% of global HCV infections. Because interferon-containing treatments for genotype 4 infection have low efficacy and poor tolerability, an unmet need exists for effective all-oral regimens. We examined the efficacy and safety of an all-oral interferon-free regimen of ombitasvir, an NS5A inhibitor, and paritaprevir (ABT-450), an NS3/4A protease inhibitor dosed with ritonavir (ombitasvir plus paritaprevir plus ritonavir), given with or without ribavirin.
  
  
  METHODS
  In this multicentre ongoing phase 2b, randomised, open-label combination trial (PEARL-I), patients were recruited from academic, public, and private hospitals and clinics in France, Hungary, Italy, Poland, Romania, Spain, Turkey, and the USA. Eligible participants were aged 18-70 years with non-cirrhotic, chronic HCV genotype 4 infection (documented ≥6 months before screening) and plasma HCV RNA levels higher than 10,000 IU/mL. Previously untreated (treatment-naive) patients were randomly assigned (1:1) by computer-generated randomisation lists to receive once-daily ombitasvir (25 mg) plus paritaprevir (150 mg) plus ritonavir (100 mg) with or without weight-based ribavirin for 12 weeks. Previously treated (treatment-experienced) patients who had received pegylated interferon plus ribavirin all received the ribavirin-containing regimen. The primary endpoint was a sustained virological response (HCV RNA <25 IU/mL) 12 weeks after the end of treatment (SVR12). Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT01685203.
  
  
  RESULTS
  Between Aug 14, 2012, and Nov 19, 2013, 467 patients with HCV infection were screened, of whom 174 were infected with genotype 4. 135 patients were randomly assigned to treatment and received at least one dose of study medication; 86 patients were treatment-naive, of whom 44 received ombitasvir plus paritaprevir plus ritonavir and 42 received ombitasvir plus paritaprevir plus ritonavir with ribavirin, and 49 treatment-experienced patients received the ribavirin-containing regimen. In previously untreated patients, SVR12 rates were 100% (42/42 [95% CI 91·6-100]) in the ribavirin-containing regimen and 90·9% (40/44 [95% CI 78·3-97·5]) in the ribavirin-free regimen. No statistically significant differences in SVR12 rates were noted between the treatment-naive groups (mean difference -9·16% [95% CI -19·61 to 1·29]; p=0·086). All treatment-experienced patients achieved SVR12 (49/49; 100% [95% CI 92·7-100]). In the ribavirin-free group, two (5%) of 42 treatment-naive patients had virological relapse, and one (2%) of 44 had virological breakthrough; no virological failures were recorded in the ribavirin-containing regimen. The most common adverse event was headache (14 [29%] of 49 treatment-experienced patients and 14 [33%] of 42 treatment-naive patients). No adverse event-related discontinuations or dose interruptions of study medications, including ribavirin, were noted, and only four patients (4%) of 91 receiving ribavirin required dose modification for haemoglobin less than 100 g/L or anaemia.
  
  
  CONCLUSIONS
  An interferon-free regimen of ombitasvir plus paritaprevir plus ritonavir with or without ribavirin achieved high sustained virological response rates at 12 weeks after the end of treatment and was generally well tolerated, with low rates of anaemia and treatment discontinuation in non-cirrhotic previously untreated and previously treated patients with HCV genotype 4 infection.
  
  
  BACKGROUND
  AbbVie.
authors.affiliation: Department of Hepatology and Gastroenterology, Hôpital Henri Mondor, AP-HP, Université Paris-Est, Inserm, Créteil, France. Electronic address: christophe.hezode@hmn.aphp.fr.
authors.forename: Christophe
authors.initials: C
authors.lastname: Hézode
authors.affiliation: Centre de Recherche sur l'Inflammation (CRI), Inserm UMR, Université Paris Diderot, Service d'Hépatologie, AP-HP Hôpital Beaujon, Clichy, France.
authors.forename: Tarik
authors.initials: T
authors.lastname: Asselah
authors.affiliation: Division of Gastroenterology and Hepatology, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: K Rajender
authors.initials: KR
authors.lastname: Reddy
authors.affiliation: Southern California Liver Centers and Southern California Research Center, Coronado, CA, USA.
authors.forename: Tarek
authors.initials: T
authors.lastname: Hassanein
authors.affiliation: Hepatology Unit, Hospital Universitario La Fe, Universidad de Valencia and Ciberehd, Valencia, Spain.
authors.forename: Marina
authors.initials: M
authors.lastname: Berenguer
authors.affiliation: Department of Infectious Disease, Liver Diseases and Acquired Immune Deficiencies, Wroclaw Medical University, Wroclaw, Poland.
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Fleischer-Stepniewska
authors.affiliation: Service d'Hépatologie, AP-HP Hôpital Beaujon, Clichy, France.
authors.forename: Patrick
authors.initials: P
authors.lastname: Marcellin
authors.affiliation: AbbVie Inc, North Chicago, IL, USA.
authors.forename: Coleen
authors.initials: C
authors.lastname: Hall
authors.affiliation: AbbVie Inc, North Chicago, IL, USA.
authors.forename: Gretja
authors.initials: G
authors.lastname: Schnell
authors.affiliation: AbbVie Inc, North Chicago, IL, USA.
authors.forename: Tami
authors.initials: T
authors.lastname: Pilot-Matias
authors.affiliation: AbbVie Inc, North Chicago, IL, USA.
authors.forename: Niloufar
authors.initials: N
authors.lastname: Mobashery
authors.affiliation: AbbVie Inc, North Chicago, IL, USA.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Redman
authors.affiliation: AbbVie Inc, North Chicago, IL, USA.
authors.forename: Regis A
authors.initials: RA
authors.lastname: Vilchez
authors.affiliation: Groupe Hospitalier Cochin-Saint Vincent De Paul, Université Paris Descartes, Inserm, Institut Pasteur, Paris, France.
authors.forename: Stanislas
authors.initials: S
authors.lastname: Pol
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000410:Alanine Transaminase / Q000187:drug effects; D000813:Anilides / Q000008:administration & dosage*; D000998:Antiviral Agents / Q000627:therapeutic use; D001219:Aspartate Aminotransferases / Q000187:drug effects; D002219:Carbamates / Q000008:administration & dosage*; D003521:Cyclopropanes; D004359:Drug Therapy, Combination; D005260:Female; D005838:Genotype; D016174:Hepacivirus / Q000235:genetics*; D019698:Hepatitis C, Chronic / Q000188:drug therapy* / Q000201:enzymology / Q000821:virology; D006801:Humans; D047029:Lactams, Macrocyclic; D047028:Macrocyclic Compounds / Q000008:administration & dosage*; D008297:Male; D008875:Middle Aged; D011392:Proline / Q000031:analogs & derivatives; D012254:Ribavirin / Q000008:administration & dosage*; D019438:Ritonavir / Q000008:administration & dosage*; D013449:Sulfonamides; D016896:Treatment Outcome; D014633:Valine; D055815:Young Adult
chemical_list: D000813:Anilides; D000998:Antiviral Agents; D002219:Carbamates; D003521:Cyclopropanes; D047029:Lactams, Macrocyclic; D047028:Macrocyclic Compounds; D013449:Sulfonamides; C586094:ombitasvir; D012254:Ribavirin; D011392:Proline; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D014633:Valine; D019438:Ritonavir; C585405:paritaprevir