Ledipasvir and sofosbuvir for previously treated HCV genotype 1 infection.
BACKGROUND
Effective treatment for hepatitis C virus (HCV) genotype 1 infection in patients who have not had a sustained virologic response to prior interferon-based therapy represents an unmet medical need.


METHODS
We conducted a phase 3, randomized, open-label study involving patients infected with HCV genotype 1 who had not had a sustained virologic response after treatment with peginterferon and ribavirin, with or without a protease inhibitor. Patients were randomly assigned to receive the NS5A inhibitor ledipasvir and the nucleotide polymerase inhibitor sofosbuvir in a once-daily, fixed-dose combination tablet for 12 weeks, ledipasvir-sofosbuvir plus ribavirin for 12 weeks, ledipasvir-sofosbuvir for 24 weeks, or ledipasvir-sofosbuvir plus ribavirin for 24 weeks. The primary end point was a sustained virologic response at 12 weeks after the end of therapy.


RESULTS
Among the 440 patients who underwent randomization and were treated, 20% had cirrhosis and 79% had HCV genotype 1a infection. The rates of sustained virologic response were high in all treatment groups: 94% (95% confidence interval [CI], 87 to 97) in the group that received 12 weeks of ledipasvir-sofosbuvir; 96% (95% CI, 91 to 99) in the group that received 12 weeks of ledipasvir-sofosbuvir and ribavirin; 99% (95% CI, 95 to 100) in the group that received 24 weeks of ledipasvir-sofosbuvir; and 99% (95% CI, 95 to 100) in the group that received 24 weeks of ledipasvir-sofosbuvir and ribavirin. No patient discontinued treatment owing to an adverse event. The most common adverse events were fatigue, headache, and nausea.


CONCLUSIONS
Treatment with a once-daily, single-tablet regimen of ledipasvir and sofosbuvir resulted in high rates of sustained virologic response among patients with HCV genotype 1 infection who had not had a sustained virologic response to prior interferon-based treatment. (Funded by Gilead Sciences; ION-2 ClinicalTrials.gov number, NCT01768286.).
From Beth Israel Deaconess Medical Center, Boston (N.A.); University of Pennsylvania, Philadelphia (K.R.R.); University of Florida, Gainesville (D.R.N.); Texas Liver Institute, University of Texas Health Science Center, San Antonio (E.L.), and the North Texas Research Institute, Arlington (R.G.) - both in Texas; Henry Ford Health Systems, Detroit (S.C.G.); Center for Liver Diseases, School of Medicine, University of Miami, Miami (E.S.); ID Care, Hillsborough, NJ (R.N.); Atlanta Gastroenterology Associates, Atlanta (N.G.); Quality Medical Research, Nashville (R.H.), and Gastro One, Germantown (Z.H.Y.) - both in Tennessee; Quest Clinical Research, San Francisco (J.L.), Scripps Clinic, La Jolla (P.J.P.), and Gilead Sciences, Foster City (G.M.S., Y.Z., H.D.-S., J.C.Y., P.S.P., W.T.S., J.G.M.) - all in California; Saint Louis University, St. Louis (A.M.D.); University of New Mexico, Albuquerque (S.A.); Duke University Medical Center, Durham, NC (A.J.M.); Johns Hopkins Medical Center, Baltimore (M.S.); and Indiana University School of Medicine, Indianapolis (P.K.).
Nezam
N
Afdhal
K Rajender
KR
Reddy
David R
DR
Nelson
Eric
E
Lawitz
Stuart C
SC
Gordon
Eugene
E
Schiff
Ronald
R
Nahass
Reem
R
Ghalib
Norman
N
Gitlin
Robert
R
Herring
Jacob
J
Lalezari
Ziad H
ZH
Younes
Paul J
PJ
Pockros
Adrian M
AM
Di Bisceglie
Sanjeev
S
Arora
G Mani
GM
Subramanian
Yanni
Y
Zhu
Hadas
H
Dvory-Sobol
Jenny C
JC
Yang
Phillip S
PS
Pang
William T
WT
Symonds
John G
JG
McHutchison
Andrew J
AJ
Muir
Mark
M
Sulkowski
Paul
P
Kwo
D000328:Adult; D000368:Aged; D000998:Antiviral Agents / Q000009:adverse effects / Q000627:therapeutic use*; D001562:Benzimidazoles / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D004338:Drug Combinations; D005260:Female; D005449:Fluorenes / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D005838:Genotype; D016174:Hepacivirus / Q000235:genetics*; D019698:Hepatitis C, Chronic / Q000188:drug therapy* / Q000821:virology; D006801:Humans; D008297:Male; D008875:Middle Aged; D009713:Nucleotidyltransferases / Q000037:antagonists & inhibitors; D012324:RNA-Dependent RNA Polymerase / Q000037:antagonists & inhibitors; D000069474:Sofosbuvir; D014542:Uridine Monophosphate / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D019562:Viral Load; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors
D000998:Antiviral Agents; D001562:Benzimidazoles; D004338:Drug Combinations; D005449:Fluorenes; D017361:Viral Nonstructural Proteins; C586541:ledipasvir; D014542:Uridine Monophosphate; D009713:Nucleotidyltransferases; C022545:ribonucleotide polymerase; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase; D000069474:Sofosbuvir