title: Efficacy and safety of danoprevir-ritonavir plus peginterferon alfa-2a-ribavirin in hepatitis C virus genotype 1 prior null responders.
abstract: Danoprevir (DNV) is a hepatitis C virus (HCV) protease inhibitor that achieves high sustained virologic response (SVR) rates in combination with peginterferon alfa-2a-ribavirin in treatment-naive HCV genotype 1 (G1)-infected patients. This study explored the efficacy and safety of ritonavir-boosted DNV (DNVr) plus peginterferon alfa-2a-ribavirin in G1-infected prior peginterferon-ribavirin null responders. Null responders (<2-log10 reduction in HCV RNA level at week 12) were given an open-label combination of 100 mg of ritonavir and 100 mg of DNV (100/100 mg DNVr) every 12 h (q12h) plus peginterferon alfa-2a-ribavirin for 12 weeks. All patients achieving an early virologic response (EVR; ≥2-log10 decrease in HCV RNA by week 12) continued treatment with peginterferon alfa-2a-ribavirin; those without an EVR discontinued all study drugs. Twenty-four prior null responders were enrolled; 16 patients (67%) were infected with HCV G1b, and 8 (33%) were infected with G1a. Ninety-six percent of patients had an IL28B non-CC genotype. A sustained virologic response at 24 weeks posttreatment (SVR24) was achieved in 67% of patients, with a higher rate in G1b-infected (88%) than G1a-infected (25%) patients. Resistance-related breakthrough occurred in 4/8 G1a and 1/16 G1b patients through the DNV resistance-associated variant (RAV) NS3 R155K. NS3 R155K was also detected in 2/2 G1a patients who relapsed. Treatment was well tolerated. Two patients withdrew prematurely from study medications due to adverse events. Two serious adverse events were reported; both occurred after completion of DNVr therapy and were considered unrelated to treatment. No grade 3 or 4 alanine aminotransferase (ALT) elevations were observed. DNVr plus peginterferon alfa-2a-ribavirin demonstrated high SVR24 rates in HCV G1b-infected prior null responders and was well tolerated. (This study has been registered at ClinicalTrials.gov under registration no. NCT01185860.).
authors.affiliation: Auckland Clinical Studies, Auckland, New Zealand.
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Gane
authors.forename: Régine
authors.initials: R
authors.lastname: Rouzier
authors.forename: Alicja
authors.initials: A
authors.lastname: Wiercinska-Drapalo
authors.forename: Dominique G
authors.initials: DG
authors.lastname: Larrey
authors.forename: Peter N
authors.initials: PN
authors.lastname: Morcos
authors.forename: Barbara J
authors.initials: BJ
authors.lastname: Brennan
authors.forename: Sophie
authors.initials: S
authors.lastname: Le Pogam
authors.forename: Isabel
authors.initials: I
authors.lastname: Nájera
authors.forename: Rosemary
authors.initials: R
authors.lastname: Petric
authors.forename: Jonathan Q
authors.initials: JQ
authors.lastname: Tran
authors.forename: Rohit
authors.initials: R
authors.lastname: Kulkarni
authors.forename: Ying
authors.initials: Y
authors.lastname: Zhang
authors.forename: Patrick
authors.initials: P
authors.lastname: Smith
authors.forename: Ellen S
authors.initials: ES
authors.lastname: Yetzer
authors.forename: Nancy S
authors.initials: NS
authors.lastname: Shulman
mesh_terms: D000328:Adult; D000410:Alanine Transaminase / Q000097:blood; D000998:Antiviral Agents / Q000008:administration & dosage* / Q000009:adverse effects; D003521:Cyclopropanes; D004334:Drug Administration Schedule; D024882:Drug Resistance, Viral / Q000187:drug effects; D004359:Drug Therapy, Combination; D005260:Female; D005838:Genotype; D016174:Hepacivirus / Q000187:drug effects / Q000502:physiology; D019698:Hepatitis C, Chronic / Q000188:drug therapy* / Q000821:virology; D006801:Humans; D016898:Interferon-alpha / Q000008:administration & dosage* / Q000009:adverse effects; D054833:Isoindoles; D007769:Lactams / Q000008:administration & dosage* / Q000009:adverse effects; D047029:Lactams, Macrocyclic; D008297:Male; D008875:Middle Aged; D009154:Mutation; D011092:Polyethylene Glycols / Q000008:administration & dosage* / Q000009:adverse effects; D011392:Proline / Q000031:analogs & derivatives; D012367:RNA, Viral / Q000037:antagonists & inhibitors* / Q000235:genetics; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000009:adverse effects; D012254:Ribavirin / Q000008:administration & dosage* / Q000009:adverse effects; D019438:Ritonavir / Q000008:administration & dosage* / Q000009:adverse effects; D013449:Sulfonamides / Q000008:administration & dosage* / Q000009:adverse effects; D016896:Treatment Outcome; D019562:Viral Load / Q000187:drug effects; D017361:Viral Nonstructural Proteins / Q000235:genetics; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
chemical_list: D000410:Alanine Transaminase; D000998:Antiviral Agents; D003521:Cyclopropanes; D016898:Interferon-alpha; D054833:Isoindoles; D007769:Lactams; D047029:Lactams, Macrocyclic; D011092:Polyethylene Glycols; D011392:Proline; D012367:RNA, Viral; D011994:Recombinant Proteins; D012254:Ribavirin; D019438:Ritonavir; D013449:Sulfonamides; D017361:Viral Nonstructural Proteins; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases; C553752:danoprevir; C100416:peginterferon alfa-2a