ABT-450/r-ombitasvir and dasabuvir with ribavirin for hepatitis C with cirrhosis.
BACKGROUND
Interferon-containing regimens for the treatment of hepatitis C virus (HCV) infection are associated with increased toxic effects in patients who also have cirrhosis. We evaluated the interferon-free combination of the protease inhibitor ABT-450 with ritonavir (ABT-450/r), the NS5A inhibitor ombitasvir (ABT-267), the nonnucleoside polymerase inhibitor dasabuvir (ABT-333), and ribavirin in an open-label phase 3 trial involving previously untreated and previously treated adults with HCV genotype 1 infection and compensated cirrhosis.


METHODS
We randomly assigned 380 patients with Child-Pugh class A cirrhosis to receive either 12 or 24 weeks of treatment with ABT-450/r-ombitasvir (at a once-daily dose of 150 mg of ABT-450, 100 mg of ritonavir, and 25 mg of ombitasvir), dasabuvir (250 mg twice daily), and ribavirin administered according to body weight. The primary efficacy end point was a sustained virologic response 12 weeks after the end of treatment. The rate of sustained virologic response in each group was compared with the estimated rate with a telaprevir-based regimen (47%; 95% confidence interval [CI], 41 to 54). A noninferiority margin of 10.5 percentage points established 43% as the noninferiority threshold; the superiority threshold was 54%.


RESULTS
A total of 191 of 208 patients who received 12 weeks of treatment had a sustained virologic response at post-treatment week 12, for a rate of 91.8% (97.5% CI, 87.6 to 96.1). A total of 165 of 172 patients who received 24 weeks of treatment had a sustained virologic response at post-treatment week 12, for a rate of 95.9% (97.5% CI, 92.6 to 99.3). These rates were superior to the historical control rate. The three most common adverse events were fatigue (in 32.7% of patients in the 12-week group and 46.5% of patients in the 24-week group), headache (in 27.9% and 30.8%, respectively), and nausea (in 17.8% and 20.3%, respectively). The hemoglobin level was less than 10 g per deciliter in 7.2% and 11.0% of patients in the respective groups. Overall, 2.1% of patients discontinued treatment owing to adverse events.


CONCLUSIONS
In this phase 3 trial of an oral, interferon-free regimen evaluated exclusively in patients with HCV genotype 1 infection and cirrhosis, multitargeted therapy with the use of three new antiviral agents and ribavirin resulted in high rates of sustained virologic response. Drug discontinuations due to adverse events were infrequent. (Funded by AbbVie; TURQUOISE-II ClinicalTrials.gov number, NCT01704755.).
From the Texas Liver Institute-University of Texas Health Science Center, San Antonio (F.P.); Henri Mondor Hospital, Assistance Publique-Hôpitaux de Paris, University Paris-Est, INSERM Unité 955, Créteil, France (C.H.); AbbVie, North Chicago, IL (R.T., S.S.L., B.D.S.-T., C.A.C., A.L.C., T.P., B.B.); Digestive Disease Institute, Virginia Mason Medical Center, Seattle (K.V.K.); Johann Wolfgang Goethe University, Frankfurt (S.Z.), Medizinische Hochschule Hannover, Hannover (H.W.), and Universitätsklinikum Leipzig, Leipzig (T.B.) - all in Germany; Institute of Liver Studies, King's College Hospital, London (K.A.); Liver Institute of Virginia, Newport News (M.L.S.); University of British Columbia, Vancouver, Canada (E.M.Y.); and Liver Unit, Hospital Clinic, Institut d'Investigacions Biomèdiques August Pi i Sunyer and Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Barcelona (X.F.).
Fred
F
Poordad
Christophe
C
Hezode
Roger
R
Trinh
Kris V
KV
Kowdley
Stefan
S
Zeuzem
Kosh
K
Agarwal
Mitchell L
ML
Shiffman
Heiner
H
Wedemeyer
Thomas
T
Berg
Eric M
EM
Yoshida
Xavier
X
Forns
Sandra S
SS
Lovell
Barbara
B
Da Silva-Tillmann
Christine A
CA
Collins
Andrew L
AL
Campbell
Thomas
T
Podsadecki
Barry
B
Bernstein
D000328:Adult; D000368:Aged; D000813:Anilides / Q000009:adverse effects / Q000627:therapeutic use*; D000998:Antiviral Agents / Q000009:adverse effects / Q000627:therapeutic use*; D002219:Carbamates / Q000009:adverse effects / Q000627:therapeutic use*; D003521:Cyclopropanes; D024882:Drug Resistance, Viral; D004359:Drug Therapy, Combination; D005260:Female; D005838:Genotype; D016174:Hepacivirus / Q000235:genetics / Q000302:isolation & purification; D019698:Hepatitis C, Chronic / Q000150:complications / Q000188:drug therapy*; D006801:Humans; D047029:Lactams, Macrocyclic; D008103:Liver Cirrhosis / Q000188:drug therapy / Q000209:etiology; D016015:Logistic Models; D047028:Macrocyclic Compounds / Q000009:adverse effects / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D011392:Proline / Q000031:analogs & derivatives; D012008:Recurrence; D012254:Ribavirin / Q000009:adverse effects / Q000627:therapeutic use*; D013449:Sulfonamides; D014633:Valine
D000813:Anilides; D000998:Antiviral Agents; D002219:Carbamates; D003521:Cyclopropanes; D047029:Lactams, Macrocyclic; D047028:Macrocyclic Compounds; D013449:Sulfonamides; C586094:ombitasvir; D012254:Ribavirin; D011392:Proline; D014633:Valine; C585405:paritaprevir